Sorbitol dehydrogenase inhibitors

ABSTRACT

This invention is directed to sorbitol dehydrogenase inhibitory compounds of the formula 1,  
                 
 
wherein R 1 , R 2  and R 3  are as defined in the specification. This invention is also directed to pharmaceutical compositions containing those compounds and methods of treating or preventing diabetic complications, particularly diabetic neuropathy, diabetic nephropathy, diabetic microangiopathy, diabetic macroangiopathy and diabetic cardiomyopathy by administering such compounds to a mammal suffering from diabetes and therefore at risk for developing such complications. This invention is also directed to pharmaceutical compositions comprising a combination of a compound of formula I of this invention with an aldose reductase inhibitor and to methods of treating or preventing diabetic complications therewith. This invention is also directed to pharmaceutical compositions comprising a combination of a compound of formula I of this invention with an NHE-1 inhibitor and to methods of, treating cardiomyopathy and other heart-related problems therewith. This invention is also directed to certain intermediates used in the synthesis of the compounds of formula I and to processes for preparing those intermediates.

BACKGROUND OF THE INVENTION

The present invention relates to novel pyrimidine derivatives and to theuse of such derivatives and related compounds to inhibit sorbitoldehydrogenaset (SDH), lower fructose levels, or treat or preventdiabetic complications such as diabetic neuropathy, diabeticretinopathy, diabetic nephropathy, diabetic cardiomyopathy, diabeticmicroangiopathy and diabetic macroangiopathy in mammals. This inventionalso relates to pharmaceutical compositions containing such pyrimidinederivatives and related compounds. This invention also relates topharmaceutical compositions comprising a combination of a sorbitoldehydrogenase inhibitor of formula I and an aldose reductase inhibitorand to the use of such compositions to treat or prevent diabeticcomplications in mammals. This invention also relates to pharmaceuticalcompositions comprising a combination of a sorbitol dehydrogenaseinhibitor of formula I and an NHE-1 inhibitor and to the use of suchcompositions to reduce tissue damage resulting from ischemia, andparticularly to prevent perioperative myocardial ischemic injury.

S. Ao et al., Metabolism, 40, 77-87 (1991) have shown that significantfunctional improvement in the nerves of diabetic rats (based on nerveconduction velocity) occurs when nerve fructose levels arepharmacologically lowered, and that such improvement correlates moreclosely with the lowering of nerve fructose than the lowering of nervesorbitol. Similar results were reported by N. E. Cameron and M. A.Cotter, Diabetic Medicine, 8, Suppl. 1, 35A-36A (1991). In both of thesecases, lowering of nerve fructose was achieved using relatively highdoes of aldose reductase inhibitors, which inhibit the formation ofsorbitol, a precursor of fructose, from glucose via the enzyme aldosereductase.

U.S. Pat. Nos. 5,138,058 and 5,215,990, which are hereby incorporated byreference, each disclose compounds of the formula

where R¹, R², R³, R⁴ and R⁵ are as disclosed therein. Said compounds aredisclosed as having utility as tools in screening for aldose reductaseinhibitors due to the sorbitol accumulating activity of said compounds.

Commonly assigned U.S. Pat. Nos. 5,728,704 and 5,866,578, which arehereby incorporated by reference, each disclose compounds of the formulaA,

wherein R¹ through R⁵ are defined as disclosed therein. Further, U.S.Pat. No. 5,728,704 discloses that sorbitol dehydrogenase compounds haveutility in the treatment of diabetic complications.

Pyrimidine derivatives of the formula I, as defined below, and theirpharmaceutically acceptable salts, lower fructose levels in the tissuesof mammals affected by diabetes (e.g., nerve, kidney and retina tissue)and are useful in the treatment and prevention of the diabeticcomplications referred to above. These compounds, or their metabolitesin vivo, are inhibitors of the enzyme sorbitol dehydrogenase, whichcatalyzes the oxidation of sorbitol to fructose.

SUMMARY OF THE INVENTION

The present invention is directed to a compound of the formula I

a prodrug thereof or a pharmaceutically acceptable salt of said compoundor said prodrug, wherein:

-   R¹ is formyl, acetyl, propionyl, carbamoyl or —C(OH)R⁴R⁵;-   R⁴ and R⁵ are each independently hydrogen, methyl, ethyl or    hydroxy-(C₁-C₃)alkyl;-   R² is hydrogen, (C₁-C₄)alkyl or (C₁-C₄)alkoxy;-   R³ is a radical of the formula-    wherein said radical of formula R^(3a) is additionally substituted    on the ring by R⁶, R⁷ and R⁸;-   said radical of formula R^(3b) is additionally substituted on the    ring by R¹⁸, R¹⁹ and R²⁰ G, G¹ and G² are taken separately and are    each hydrogen and R⁶ is hydrogen, (C₁-C₄)alkyl,    (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl,    hydroxy-(C₁-C₄)alkyl or phenyl optionally independently substituted    with up to three hydroxy, halo, hydroxy(C₁-C₄)alkyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl or (C₁-C₄)alkoxy, wherein    said (C₁-C₄)alkyl in the definition of R⁶ and said (C₁-C₄)alkoxy in    the definition of R⁶ are optionally and independently substituted    with up to five fluoro; R⁷ and R⁸ are each independently hydrogen or    (C₁-C₄)alkyl; or-   G and G¹ are taken together and are (C₁-C₃)alkylene and R⁶, R⁷, R⁸    and G² are hydrogen; or-   G¹ and G² are taken together and are (C₁-C₃)alkylene and R⁶, R⁷, R⁸    and G are hydrogen;-   q is 0 or 1;-   X is a covalent bond, —(C═NR¹⁰)—, oxycarbonyl, vinylenylcarbonyl,    oxy(C₁-C₄)alkylenylcarbonyl, (C₁-C₄)alkylenylcarbonyl,    (C₃-C₄)alkenylcarbonyl, thio(C₁-C₄)alkylenylcarbonyl,    vinylenylsulfonyl, sulfinyl-(C₁-C₄)alkylenylcarbonyl,    sulfonyl-(C₁-C₄)alkylenylcarbonyl or    carbonyl(C₀-C₄)alkylenylcarbonyl; wherein said    oxy(C₁-C₄)alkylenylcarbonyl, (C₁-C₄)alkylenylcarbonyl,    (C₃-C₄)alkenylcarbonyl and thio(C₁-C₄)alkylenylcarbonyl in the    definition of X are each optionally and independently substituted    with up to two (C₁-C₄)alkyl, benzyl or Ar; said vinylenylsulfonyl    and said vinylenylcarbonyl in the definition of X are optionally    substituted independently on one or two vinylenyl carbons with    (C₁-C₄)alkyl, benzyl or Ar; and said    carbonyl(C₀-C₄)alkylenylcarbonyl in the definition of X is    optionally substituted independently with up to three (C₁-C₄)alkyl,    benzyl or Ar;-   R¹⁰ is hydrogen or (C₁-C₄)alkyl;-   R⁹ is (C₃-C₇)cycloalkyl, Ar¹—(C₀-C₃)alkylenyl or (C₁-C₆)alkyl    optionally substituted with up to five fluoro; provided that when    q=0 and X is a covalent bond, oxycarbonyl or    (C₁-C₄)alkylenylcarbonyl, then R⁹ is not (C₁-C₆)alkyl;-   Ar and Ar¹ are independently a fully saturated, partially saturated    or fully unsaturated five- to eight-membered ring optionally having    up to four heteroatoms selected independently from oxygen, sulfur    and nitrogen, or a bicyclic ring consisting of two fused    independently partially saturated, fully saturated or fully    unsaturated five- to seven-membered rings, taken independently,    optionally having up to four heteroatoms selected independently from    nitrogen, sulfur and oxygen, or a tricyclic ring consisting of three    fused independently partially saturated, fully saturated or fully    unsaturated five to seven membered rings, taken independently,    optionally having up to four heteroatoms selected independently from    nitrogen, sulfur and oxygen, said partially saturated, fully    saturated ring or fully unsaturated monocyclic ring, bicyclic ring    or tricyclic, ring optionally having one or two oxo groups    substituted on carbon or one or two oxo groups substituted on    sulfur;-   Ar and Ar¹ are optionally independently substituted on carbon or    nitrogen, on one ring if the moiety is monocyclic, on one or both    rings if the moiety is bicyclic, or on one, two or three rings if    the moiety is tricyclic, with up to a total of four substituents    independently selected from R¹¹, R¹², R¹³ and R¹⁴; wherein R¹¹, R¹²,    R¹³ and R¹⁴ are each taken separately and are each independently    halo, formyl, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylenyloxycarbonyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, C(OH)R¹⁵R¹⁶, naphthyl, phenyl,    imidazolyl, pyridyl, triazolyl, morpholinyl, (C₀-C₄)alkylsulfamoyl,    N-(C₀-C₄)alkylcarbamoyl, N,N-di-(C₁-C₄)alkylcarbamoyl,    N-phenylcarbamoyl, N-(C₁-C₄)alkyl-N-phenylcarbamoyl, N,N-diphenyl    carbamoyl, (C₁-C₄)alkylcarbonylamido,    (C₃-C₇)cycloalkylcarbonylamido, phenylcarbonylamido, piperidinyl,    pyrrolidinyl, piperazinyl, cyano benzimidazolyl, amino, anilino,    pyrimidyl, oxazolyl, isoxazolyl, tetrazolyl, thienyl, thiazolyl,    benzothiazolyl, pyrrolyl, pyrazolyl, tetrahydroquinolyl,    tetrahydroisoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy,    pyridylsulfanyl, furanyl,    8-(C₁-C₄)alkyl-3,8-diaza[3.2.1]bicyclooctyl, 3,5-dioxo-1,2,4    triazinyl, phenoxy, thiophenoxy, (C₁-C₄)alkylsulfanyl,    (C₁-C₄)alkylsulfonyl, (C₃-C₇)cycloalkyl, (C₁-C₄)alkyl optionally    substituted with up to five fluoro or (C₁-C₄)alkoxy optionally    substituted with up to five fluoro; said naphthyl, phenyl, pyridyl,    piperidinyl, benzimidazolyl, pyrimidyl, thienyl, benzothiazolyl,    pyrrolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzoxazolyl,    pyridazinyl, pyridyloxy, pyridylsulfanyl, furanyl, thiophenoxy,    anilino and phenoxy in the definition of R¹¹, R¹², R¹³ and R¹⁴ are    optionally substituted with up to three substituents independently    selected from hydroxy, halo, hydroxy-(C₁-C₄)alkyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally substituted with    up to five fluoro and (C₁-C₄)alkoxy optionally substituted with up    to five fluoro; said imidazolyl, oxazolyl, isoxazolyl, thiazolyl and    pyrazolyl in the definition of R¹¹, R¹², R¹³ and R¹⁴ are optionally    substituted with up to two substituents independently selected from    hydroxy, halo, hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl,    (C₁-C₄)alkyl optionally substituted with up to five fluoro and    (C₁-C₄)alkoxy optionally substituted with up to five fluoro; said    morpholinyl in the definition of R¹¹, R¹², R¹³ and R¹⁴ is optionally    substituted with up to two substituents independently selected from    (C₁-C₄)alkyl; said pyrrolidinyl in the definition of R¹¹, R¹², R¹³    and R¹⁴ is optionally substituted with up to two substituents    independently selected from hydroxy, hydroxy-(C₁-C₃)alkyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally substituted with    up to five fluoro and (C₁-C₄)alkoxy optionally substituted with up    to five fluoro; said piperazinyl in the definition of R¹¹, R¹², R¹³    and R¹⁴ is optionally substituted with up to three substituents    independently selected from (C₁-C₄)alkoxy(C₁-C₄)alkyl,    hydroxy-(C₁-C₃)alkyl, phenyl, pyridyl, (C₀-C₄)alkylsulfamoyl,    (C₁-C₄)alkyl optionally substituted with up to five fluoro and    (C₁-C₄)alkoxy optionally substituted with up to five fluoro; said    triazolyl in the definition of R¹¹, R¹², R¹¹³ and R¹⁴ is optionally    substituted with hydroxy, halo, hydroxy-(C₁-C₄)alkyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally substituted with    up to five fluoro and (C₁-C₄)alkoxy optionally substituted with up    to five fluoro; said tetrazolyl in the definition of R¹¹, R¹², R¹³    and R¹⁴ is optionally substituted with hydroxy-(C₂-C₃)alkyl or    (C₁-C₄)alkyl optionally substituted with up to five fluoro; and said    phenyl and pyridyl which are optionally substituted on piperazine in    the definition of R¹¹, R¹², R¹³ and R¹⁴ are optionally substituted    with up to three hydroxy, halo, hydroxy-(C₁-C₄)alkyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally substituted with    up to five fluoro and (C₁-C₄)alkoxy optionally substituted with up    to five fluoro; or-   R¹¹ and R¹² are taken together on adjacent carbon atoms and are    —CH₂OC(CH₃)₂OCH₂— or —O—(CH₂)_(p)—O—, and R¹³ and R¹⁴ are taken    separately and are each independently hydrogen or (C₁-C₄)alkyl;-   p is 1, 2 or 3;-   R¹⁵ and R¹⁶ are taken separately and are each independently    hydrogen, (C₁-C₄)alkyl optionally substituted with up to five    fluoro; or R¹⁵ and R¹⁶ are taken separately and-   R¹⁵ is hydrogen and R¹⁶ is (C₃-C₆)cycloalkyl, hydroxy-(C₁-C₃)alkyl,    phenyl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl, oxazolyl,    imidazolyl, benzothiazolyl or benzoxazolyl; or R¹⁵ and R¹⁶ are taken    together and are (C₃-C₆)alkylene;-   G³, G⁴ and G⁵ are taken separately and are each hydrogen; r is 0;    R¹⁸ is hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxycarbonyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, hydroxy-(C₁-C₄)alkyl or phenyl    optionally independently substituted with up to three hydroxy, halo,    hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl or    (C₁-C₄)alkoxy, wherein said (C₁-C₄)alkyl in the definition of R⁶ and    said (C₁-C₄)alkoxy in the definition of R⁶ are optionally and    independently substituted with up to five fluoro; and R¹⁹ and R²⁰    are each independently (C₁-C₄)alkyl; or-   G³, G⁴ and G⁵ are taken separately and are each hydrogen; r is 1;    R¹⁸ is hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxycarbonyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, hydroxy-(C₁-C₄)alkyl or phenyl    optionally independently substituted with up to three hydroxy, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl or    (C₁-C₄)alkoxy, wherein said (C₁-C₄)alkyl in the definition of R⁶ and    said (C₁-C₄)alkoxy in the definition of R⁶ are optionally and    independently substituted with up to five fluoro; and R¹⁹ and R²⁰    are each independently hydrogen or (C₁-C₄)alkyl; or-   G³ and G⁴ are taken together and are (C₁-C₃)alkylene; r is 0 or 1;    and R¹⁸, R¹⁹, R²⁰ and G⁵ are hydrogen; or-   G⁴ and G⁵ are taken together and are (C₁-C₃)alkylene; r is 0 or 1;    and R¹⁸, R¹⁹, R²⁰ and G³ are hydrogen;-   R¹⁷ is SO₂NR²¹R²², CONR²¹R²², (C₁-C₆)alkoxycarbonyl,    (C₁-C₆)alkylcarbonyl, Ar²-carbonyl, (C₁-C₆)alkylsulfonyl,    (C₁-C₆)alkylsulfinyl, Ar²-sulfonyl, Ar²-sulfinyl and (C₁-C₆)alkyl;-   R²¹ and R²² are taken separately and are each independently selected    from hydrogen, (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl and    Ar²—(C₀-C₄)alkylenyl; or-   R²¹ and R²² are taken together with the nitrogen atom to which they    are attached to form azetidinyl, pyrrolidinyl, piperidinyl,    piperazinyl, morpholinyl, azepinyl, azabicyclo[3.2.2]nonanyl,    azabicyclo[2.2.1]heptyl, 6,7-dihydro-5H-dibenzo[c,e]azepinyl,    1,2,3,4-tetrahydro-isoquinolyl or    5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl; said azetidinyl in the    definition of R²¹ and R²² is optionally substituted independently    with one substituent selected from hydroxy, amino,    hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro and (C₁-C₄)alkoxy    optionally substituted with up to five fluoro; said pyrrolidinyl,    piperidinyl, azepinyl in the definition of R²¹ and R²² are    optionally substituted independently with up to two substituents    independently selected from hydroxy, amino, hydroxy-(C₁-C₄)alkyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally substituted with    up to five fluoro and (C₁-C₄)alkoxy optionally substituted with up    to five fluoro; said morpholinyl in the definition of R²¹ and R²² is    optionally substituted with up to two substituents independently    selected from hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl,    (C₁-C₄)alkyl optionally substituted with up to five fluoro and    (C₁-C₄)alkoxy optionally substituted with up to five fluoro; said    piperazinyl in the definition of R²¹ and R²² is optionally    substituted independently with up to three substituents    independently selected from phenyl, pyridyl, pyrimidyl,    (C₁-C₄)alkoxycarbonyl and (C₁-C₄)alkyl optionally substituted with    up to five fluoro; said 1,2,3,4-tetrahydro-isoquinolyl and said    5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl in the definition of R²¹    and R²² are optionally substituted independently with up to, three    substituents independently selected from hydroxy, amino, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro and (C₁-C₄)alkoxy    optionally substituted with up to five fluoro; and said    6,7-dihydro-5H-dibenzo[c,e]azepinyl in the definition of R²¹ and R²²    is optionally substituted with up to four substituents independently    selected from hydroxy, amino, halo, hydroxy-(C₁-C₄)alkyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally substituted with    up to five fluoro and (C₁-C₄)alkoxy optionally substituted with up    to five fluoro; said pyrimidyl, pyridyl and phenyl which are    optionally substituted on said piperazine in the definition of R²¹    and R²² is optionally substituted with up to three substituents    selected from hydroxy, amino, hydroxy-(C₁-C₄)alkyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl, optionally substituted    with up to five fluoro and (C₁-C₄)alkoxy optionally substituted with    up to five fluoro;-   Ar² is independently defined as set forth for Ar and Ar¹ above;-   said Ar² is optionally independently substituted as set forth for Ar    and Ar¹ above;-   R²³ is CONR²⁵R²⁶ or SO₂R²⁵R²⁶, wherein R²⁵ is hydrogen (C₁-C₄)alkyl    or Ar³—(C₀-C₄)alkylenyl and R²⁶ is Ar³—(C₀-C₄)alkylenyl; provided    that when Ar³ is phenyl, naphthyl or biphenyl, then R²³ cannot be    CONR²⁵R²⁶ where R²⁵ is hydrogen or Ar³ and R²⁶ is Ar³;-   R²⁴ is hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxycarbonyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, hydroxy-(C₁-C₄)alkyl or phenyl    optionally independently substituted with up to three hydroxy, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl or    (C₁-C₄)alkoxy, wherein said (C₁-C₄)alkyl in the definition of R⁶ and    said (C₁-C₄)alkoxy in the definition of R⁶ are optionally and    independently substituted with up to five fluoro;-   Ar³ is independently defined as set forth for Ar and Ar¹ above;-   said Ar³ is optionally independently substituted as set forth for Ar    and Ar¹ above;-   R²⁷ is hydrogen or (C₁-C₄)alkyl; R²⁸ and R² are each independently    hydrogen, hydroxy, halo, hydroxy-(C₁-C₄)alkyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally substituted with    up to five fluoro, (C₁-C₄)alkoxy optionally substituted with up to    five fluoro, phenyl, pyridyl, pyrimidyl, thienyl, furanyl,    thiazolyl, oxazolyl, phenoxy, thiophenoxy, SO₂NR³⁰R³¹, CONR³⁰R³¹ or    NR³⁰R³¹ said thienyl, pyrimidyl, furanyl, thiazolyl and oxazolyl in    the definition of R²⁸ and R²⁹ are optionally substituted by up to    two hydroxy, halo, hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl,    (C₁-C₄)alkyl optionally substituted with up to five fluoro or    (C₁-C₄)alkoxy optionally substituted with up to five fluoro; said    phenyl, pyridyl, phenoxy and thiophenoxy in the definition of R²⁸    and R²⁹ are optionally substituted by up to three hydroxy, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro or (C₁-C₄)alkoxy    optionally substituted with up to five fluoro;-   R³⁰ and R³¹ are each independently hydrogen, (C₁-C₄)alkyl,    (C₃-C₇)cycloalkyl or phenyl, said phenyl is optionally substituted    with up to three hydroxy, halo, hydroxy-(C₁-C₄)alkyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally substituted with    up to five fluoro or (C₁-C₄)alkoxy optionally substituted with up to    five fluoro; or-   R³⁰ and R³¹ are taken together with the nitrogen to which they are    attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl    or morpholinyl; said pyrrolidinyl and piperidinyl in the definition    of R³⁰ and R³¹ are optionally substituted with up to two hydroxy,    amino, hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl,    (C₁-C₄)alkyl optionally substituted with up to five fluoro or    (C₁-C₄)alkoxy optionally substituted with up to five fluoro; said    indolinyl and piperazinyl in the definition of R³⁰ and R³¹ are    optionally substituted with up to three hydroxy, amino,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl,    (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl optionally substituted with up    to five fluoro or (C₁-C₄)alkoxy optionally substituted with up to    five fluoro; said morpholinyl in the definition of R³⁰ and R³¹ is    optionally substituted with up to two substituents independently    selected from hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl,    (C₁-C₄)alkyl optionally substituted with up to five fluoro and    (C₁-C₄)alkoxy optionally substituted with up to five fluoro;-   A is N optionally substituted with hydrogen or (C₁-C₄)alkyl and B is    carbonyl; or-   A is carbonyl and B is N optionally substituted with hydrogen or    (C₁-C₄)alkyl;-   R³² is hydrogen or (C₁-C₄)alkyl;-   R³³ is phenyl, pyridyl, pyrimidyl, thiazolyl, oxazolyl, benzyl,    quinolyl, isoquinolyl, phthalizinyl, quinoxanlyl, benzothiazoyl,    benzoxazolyl, benzofuranyl or benzothienyl; said phenyl, pyridyl,    pyrimidyl, thiazolyl, oxazolyl, benzyl, quinolyl, isoquinolyl,    phthalizinyl, quinoxanlyl, benzothiazoyl, benzoxazolyl, benzofuranyl    and benzothienyl in the definition of R³³ are optionally substituted    with up to three phenyl, phenoxy, NR³⁴R³⁵, halo, hydroxy,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro or (C₁-C₄)alkoxy    optionally substituted with up to five fluoro;-   R³⁴ and R³⁵ are each independently hydrogen, (C₁-C₄ alkyl), phenyl    or phenylsulfonyl;-   said phenyl and phenylsulfonyl in the definition of R³⁴ and R³⁵ are    optionally substituted with up to three halo, hydroxy, (C₁-C₄)alkyl    optionally substituted with up to five fluoro or (C₁-C₄)alkoxy    optionally substituted with up to five fluoro;-   D is CO, CHOH or CH₂;-   E is O, NH or S;-   R³⁶ and R³⁷ are taken separately and are each independently    hydrogen, halo, cyano, hydroxy, amino, (C₁-C₆)alkylamino,    di-(C₁-C₆)alkylamino, pyrrolidino, piperidino, morpholino,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, hydroxy-(C₁-C₄)alkyl, Ar⁴, (C₁-C₄)alkyl    optionally substituted with up to five fluoro or (C₁-C₄)alkoxy    optionally substituted with up to five fluoro;-   R³⁸, R³⁹ and R⁴⁰ are each independently hydrogen or (C₁-C₄)-alkyl;-   Ar⁴ is phenyl, furanyl, thienyl, pyridyl, pyrimidyl, pyrazinyl or    pyridazinyl; said Ar⁴ being optionally substituted with up to three    hydroxy, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, halo, hydroxy-(C₁-C₄)alkyl,    (C₁-C₄)alkyl optionally substituted with up to five fluoro or    (C₁-C₄)alkoxy optionally substituted with up to five fluoro; or R³⁶    and R³⁷ are taken together on adjacent carbon atoms and are    —O—(CH₂)_(t)—O—;-   t is 1, 2 or 3;-   Y is (C₂-C₆)alkylene;-   R⁴⁴, R⁴⁵ and R⁴⁶ are each independently hydrogen or (C₁-C₄)alkyl;-   m and n are each independently 1, 2 or 3, provided that the sum of m    and n is 2, 3 or 4;-   k is 0, 1, 2, 3 or 4;-   Y¹ is a covalent bond, carbonyl, sulfonyl or oxycarbonyl;-   R⁴³ is (C₃-C₇)cycloalkyl, Ar⁵—(C₀-C₄)alkylenyl, NR⁴⁷R⁴ or    (C₁-C₆)alkyl optionally substituted with one to five fluoro;    provided that when Y¹ is a covalent bond or oxycarbonyl, then R⁴³ is    not NR⁴⁷R⁴⁸;-   R⁴⁷ and R⁴⁸ are taken separately and are each independently selected    from hydrogen, Ar⁵, (C₁-C₆)alkyl and Ar⁵—(C₀-C₄)alkylenyl; or-   R⁴⁷ and R⁴ are taken together with the nitrogen atom to which they    are attached to form azetidinyl, pyrrolidinyl, piperidinyl,    piperazinyl, morpholinyl, azepinyl, azabicyclo[3.2.2]nonanyl,    azabicyclo[2.2.1]heptyl, 1,2,3,4-tetrahydroisoquinolyl,    6,7-dihydro-5H-dibenzo[c,e]azepinyl or    5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl; said azetidinyl in the    definition of R⁴⁷ and R⁴⁸ are optionally substituted with one    hydroxy, amino, hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl,    (C₁-C₄)alkyl optionally substituted with up to five fluoro or    (C₁-C₄)alkoxy optionally substituted with up to five fluoro; said    pyrrolidinyl, piperidinyl and azepinyl in the definition of R⁴⁷ and    R⁴⁸ are optionally substituted with up to two hydroxy, amino,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro or (C₁-C₄)alkoxy    optionally substituted with up to five fluoro; said morpholinyl in    the definition of R⁴⁷ and R⁴⁸ is optionally substituted with up to    two substituents independently selected from hydroxy-(C₁-C₄)alkyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally substituted with    up to five fluoro and (C₁-C₄)alkoxy optionally substituted with up    to five fluoro; said piperazinyl, 1,2,3,4-tetrahydroisoquinolyl and    5,6,7,8-tetrahydro[4,3-d]pyrimidyl in the definition of R⁴⁷ and R⁴⁸    are optionally substituted with up to three hydroxy, amino, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro or (C₁-C₄)alkoxy    optionally substituted with up to five fluoro; and said    6,7-dihydro-5H-dibenzo[c,e]azepinyl in the definition of R⁴⁷ and R⁴⁸    are optionally substituted with up to four hydroxy, amino, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro or (C₁-C₄)alkoxy    optionally substituted with up to five fluoro;-   Ar⁵ is independently defined as set forth for Ar and Ar¹ above;-   Ar⁵ is optionally independently substituted as set forth for Ar and    Ar¹ above;-   R⁴² and R^(42a) are independently hydrogen, (C₃-C₇)cycloalkyl,    Ar⁶—(C₀-C₃)alkylenyl, Ar⁶—(C₂-C₄)alkenyl, Ar⁶-carbonyl or    (C₁-C₆)alkyl optionally substituted with up to five fluoro;-   Ar⁶ is independently defined as set forth for Ar and Ar¹ above;-   Ar⁶ is optionally independently substituted as set forth for Ar and    Ar¹ above; and-   R⁴¹ and R^(41a) are each independently hydrogen or {C₁-C₄)alkyl.

A preferred group of compounds of formula I, designated Group A, arethose compounds of formula I, prodrugs thereof and pharmaceuticallyacceptable salts of said compounds or said prodrugs, wherein:

-   R³ is    substituted by R¹⁸, R¹⁹ or R²⁰;

G³, G⁴ and G⁵ are taken separately and are each hydrogen, r is 0 and R¹¹is hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxycarbonyl or phenyl optionallysubstituted by up to three hydroxy, halo, hydroxy-(C₁-C₄)alkyl,(C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally substituted with upto five fluoro or (C₁-C₄)alkoxy optionally substituted with up to fivefluoro; R¹⁹, and R²⁰ are each independently (C₁-C₄)alkyl;

-   G³, G⁴ and G⁵ are taken separately and are, each hydrogen; r is 1;    and R¹⁸ is hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxycarbonyl dr phenyl    optionally substituted by up to three hydroxy, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro or (C₁-C₄)alkoxy    optionally substituted with up to five fluoro; R¹⁹ and R²⁰ are each    independently hydrogen or (C₁-C₄)alkyl; or G³ and G⁴ are taken    together and are (C₁-C₃)alkylene; r is 0 or 1; and R¹⁸, R¹⁹, R²⁰ and    G⁵ are hydrogen; or-   G⁴ and G⁵ are taken together and are (C₁-C₃)alkylene; r is 0 or 1;    and R¹⁸, R¹⁹, R²⁰ and G³ are hydrogen;-   R¹⁷ is SO₂NR²¹R²², CONR²¹R²², (C₁-C₆)alkoxycarbonyl,    (C₁-C₆)alkylcarbonyl, Ar²-carbonyl, (C₁-C₆)alkylsulfonyl,    (C₁-C₆)alkylsulfinyl, Ar²-sulfonyl, Ar²-sulfinyl and (C₁-C₆)alkyl;-   R²¹ and R²² are taken separately and are each independently selected    from hydrogen, (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl and    Ar²—(C₀-C₄)alkylenyl; or-   R²¹ and R²² are taken together with the nitrogen atom to which they    are attached to form azetidinyl, pyrrolidinyl, piperidinyl,    piperazinyl, morpholinyl, azepinyl, azabicyclo[3.2.2]nonanyl,    azabicyclo[2.2.1]heptyl, 6,7-dihydro-5H-dibenzo[c,e]azepinyl,    1,2,3,4-tetrahydro-isoquinolyl or    5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl; said azetidinyl in the    definition of R²¹ and R²² is optionally substituted independently    with one substituent selected from hydroxy, amino,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro and (C₁-C₄)alkoxy    optionally substituted with up to five fluoro; said pyrrolidinyl,    piperidinyl, morpholinyl, azepinyl in the definition of R²¹ and R²²    are optionally substituted independently with up to two substituents    independently selected from hydroxy, amino, hydroxy-(C₁-C₄)alkyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally substituted with    up to five fluoro and (C₁-C₄)alkoxy optionally substituted with up    to five fluoro; said morpholinyl in the definition of R²¹ and R²² is    optionally substituted with up to two substituents independently    selected from hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl,    (C₁-C₄)alkyl optionally substituted with up to five fluoro and    (C₁-C₄)alkoxy optionally substituted with up to five fluoro; said    piperazinyl in the definition of R²¹ and R²² is optionally    substituted independently with up to three substituents    independently selected from phenyl, pyridyl, pyrimidyl,    (C₁-C₄)alkoxycarbonyl and (C₁-C₄)alkyl optionally substituted with    up to five fluoro; said 1,2,3,4-tetrahydro-isoquinolyl and said    5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl in the definition of R²¹    and R²² are optionally substituted independently with up to three    substituents independently selected from hydroxy, amino, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro and (C₁-C₄)alkoxy    optionally substituted with up to five fluoro; said pyrimidyl,    pyridyl and phenyl which are optionally substituted on said    piperazine in the definition of R²¹ and R²² is optionally    substituted with up to three substituents selected from hydroxy,    amino, hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl,    (C₁-C₄)alkyl optionally substituted with up to five fluoro and    (C₁-C₄)alkoxy optionally substituted with up to five fluoro; and    said 6,7-dihydro-5H-dibenzo[c,e]azepinyl in the definition of R²¹    and R²² is optionally substituted with up to four substituents    independently selected from hydroxy, amino, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro and (C₁-C₄)alkoxy    optionally substituted with up to five fluoro.

Another preferred group of compounds of formula I, designated Group B,are those compounds of formula I, prodrugs thereof and pharmaceuticallyacceptable salts of said compounds or said prodrugs, wherein:

-   R³ is-   R²³ is CONR²⁵R²⁶, SO₂R²⁵R²⁶, wherein R²⁵ is hydrogen (C₁-C₄)alkyl or    Ar³—(C₀-C₄)alkylenyl and R²⁶ is Ar³—(C₀-C₄)alkylenyl; provided that    when Ar³ is phenyl, naphthyl or biphenyl, then R²³, cannot be    CONR²⁵R²⁶ where R²⁵ is hydrogen or Ar³ and R²⁶ is Ar³;-   R²⁴ is hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxycarbonyl or phenyl    optionally substituted by up to three (C₁-C₄)alkyl optionally    substituted with up to five fluoro, (C₁-C₄)alkoxy optionally    substituted with up to five fluoro, hydroxy, halo or    hydroxy-(C₁-C₃)alkyl.

Another Preferred group of compounds of formula I, designated Group C,are those compounds of formula I, prodrugs thereof, and pharmaceuticallyacceptable salts of said compounds or said prodrugs, wherein:

-   R³ is-   R²⁷ is hydrogen or (C₁-C₄)alkyl;-   R²⁸ and R²⁹ are each independently hydrogen, hydroxy, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro, (C₁-C₄)alkoxy    optionally substituted with up to five fluoro, phenyl, pyridyl,    pyrimidyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy,    thiophenoxy, SO₂NR³⁰, R³¹, CONR³⁰R³¹ or NR³⁰R³¹; said thienyl,    pyrimidyl, furanyl, thiazolyl and oxazolyl in the definition of R²⁸    and R²⁹ are optionally substituted by up to two hydroxy, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro or (C₁-C₄)alkoxy    optionally substituted with up to five fluoro; said phenyl, pyridyl,    phenoxy and thiophenoxy in the definition of R²⁸ and R² are    optionally substituted by up to three hydroxy, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro or (C₁-C₄)alkoxy    optionally substituted with up to five fluoro;-   R³⁰ and R³¹ are each independently hydrogen, (C₁-C₄)alkyl,    (C₃-C₇)cycloalkyl or phenyl, said phenyl is optionally substituted    with up to three hydroxy, halo, hydroxy(C₁-C₄)alkyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally substituted with    up to five fluoro or (C₁-C₄)alkoxy optionally substituted with up to    five fluoro; or-   R³⁰ and R³¹ are taken together with the nitrogen to which they are    attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl    or morpholinyl; said pyrrolidinyl and piperidinyl in the definition    of R³⁰ and R³¹ are optionally substituted with up to two hydroxy,    amino, hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl,    (C₁-C₄)alkyl optionally substituted with up to five fluoro or    (C₁-C₄)alkoxy optionally substituted with up to five fluoro; said    indolinyl and piperazinyl in the definition of R³ and R³¹ are    optionally substituted with up to three hydroxy, amino, or    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl,    (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl optionally substituted with up    to five fluoro or (C₁-C₄)alkoxy optionally substituted with up to    five fluoro; said morpholinyl in the definition of R³⁰ and R³¹ is    optionally substituted with up to two substituents independently    selected from hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl,    (C₁-C₄)alkyl optionally substituted with up to five fluoro and    (C₁-C₄)alkoxy optionally substituted with up to five fluoro.

Yet another preferred group of compounds of formula I, designated GroupD, are those compounds of formula I, prodrugs thereof andpharmaceutically acceptable salts of said compounds or said prodrugs,wherein:

-   R³ is-   A is N optionally substituted with hydrogen or (C₁-C₄)alkyl and B is    carbonyl; or-   A is carbonyl and B is N optionally substituted with hydrogen or    (C₁-C₄)alkyl;-   R³² is hydrogen or (C₁-C₄)alkyl;-   R³³ is phenyl, pyridyl, pyrimidyl, thiazolyl, oxazolyl, benzyl,    quinolyl, isoquinolyl, phthalizinyl, quinoxanlyl, benzothiazoyl,    benzoxazolyl, benzofuranyl or benzothienyl; said phenyl, pyridyl,    pyrimidyl, thiazolyl, oxazolyl, benzyl, quinolyl, isoquinolyl,    phthalizinyl, quinoxanlyl, benzothiazoyl, benzoxazolyl, benzofuranyl    and benzothienyl in the definition of R³³ are optionally substituted    with up to three phenyl, phenoxy, NR³⁴R³⁵, halo, hydroxy,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro or (C₁-C₄)alkoxy    optionally substituted with up to five fluoro;-   R³⁴ and R³⁵ are each independently hydrogen, (C₁-C₄ alkyl), phenyl    or phenylsulfonyl; said phenyl and phenylsulfonyl in the definition    of R³⁴ and R³ are optionally substituted with up to three halo,    hydroxy, (C₁-C₄)alkyl optionally substituted with up to five fluoro    or (C₁-C₄)alkoxy optionally substituted with up to five fluoro.

Still another preferred group of compounds of formula I, designatedGroup E, are those compounds of formula I, prodrugs thereof andpharmaceutically acceptable salts of said compounds or said prodrugs,wherein:

-   R³ is-   D is CO, CHOH or CH₂;-   E is O, NH or S;-   R³⁶ and R³⁷ are taken separately and are each independently    hydrogen, halo, cyano, hydroxy, amino, (C₁-C₆)alkylamino,    di-(C₁-C₆)alkylamino, pyrrolidino, piperidino, morpholino,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, hydroxy-(C₁-C₄)alkyl, Ar⁴, (C₁-C₄)alkyl    optionally substituted with up to five fluoro or (C₁-C₄)alkoxy    optionally substituted with up to five fluoro;-   R³⁸, R³⁹ and R⁴⁰ are each independently hydrogen or (C₁-C₄)-alkyl;    Ar⁴ is phenyl, furanyl, thienyl, pyridyl, pyrimidyl, pyrazinyl or    pyridazinyl; said Ar⁴ being optionally substituted with up to three    hydroxy, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, halo, hydroxy-(C₁-C₄)alkyl,    (C₁-C₄)alkyl optionally substituted with up to five fluoro or    (C₁-C₄)alkoxy optionally substituted with up to five fluoro; or-   R³⁶ and R³⁷ are taken together on adjacent carbon atoms and are    —O—(CH₂)_(t)—O—;-   t is 1, 2 or 3.

Still another preferred group of compounds of formula I, designatedGroup F, are those compounds of formula I, prodrugs thereof andpharmaceutically acceptable salts of said compounds or said prodrugs,wherein:

-   R³ is-   Y is (C₂-C₆)alkylene;-   R⁴⁴, R⁴⁵ and R⁴⁶ are each independently hydrogen or (C₁-C₄)alkyl;-   m and n are each independently 1, 2 or 3, provided that the sum of m    and n is 2, 3 or 4;-   k is 0 to 4;-   Y¹ is a covalent bond, carbonyl, sulfonyl or oxycarbonyl;-   R⁴³ is (C₃-C₇)cycloalkyl, Ar⁵—(C₀-C₄)alkylenyl, NR⁴⁷R⁴⁸ or    (C₁-C₆)alkyl optionally substituted with one to five fluoro;    provided that when Y¹ is a covalent bond or oxycarbonyl, then R⁴³ is    not NR⁴⁷R⁴;-   R⁴⁷ and R⁴ are taken separately and are each independently selected    from hydrogen, Ar⁵, (C₁-C₆)alkyl and Ar⁵—(₀-C₄)alkylenyl; or-   R⁴⁷ and 4 ar Taken together with the nitrogen atom to which they are    attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,    morpholinyl, azepinyl, azabicyclo[3.2.2]nonanyl,    azabicyclo[2.2.1]heptyl, 1,2,3,4-tetrahydroisoquinolyl,    6,7-dihydro-5H-dibenzo[c,e]azepinyl or    5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl; said azetidinyl in the    definition of R⁴⁷ and R⁴ are optionally substituted with one    hydroxy, amino, hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl,    (C₁-C₄)alkyl optionally substituted with up to five fluoro or    (C₁-C₄)alkoxy optionally substituted with up to five fluoro; said    pyrrolidinyl, piperidinyl and azepinyl in the definition of R⁴⁷ and    R⁴⁸ are optionally substituted with up to two hydroxy, amino,    hydroxy-4-C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro or (C₁-C₄)alkoxy    optionally substituted with up to five fluoro; said morpholinyl in    the definition of R⁴⁷ and R⁴⁸ is optionally substituted with up to    two substituents independently selected from hydroxy-(C₁-C₄)alkyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally, substituted    with up to five fluoro and (C₁-C₄)alkoxy optionally substituted with    up to five fluoro; said piperazinyl, 1,2,3,4-tetrahydroisoquinolyl    and 5,6,7,8-tetrahydro[4,3-d]pyrimidyl in the definition of R⁴⁷ and    R⁴ are optionally substituted with up to three hydroxy, amino, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro or (C₁-C₄)alkoxy    optionally substituted with up to five fluoro; and said    6,7-dihydro-5H-dibenzo[c,e]azepinyl in the definition of R⁴⁷ and R⁴    are optionally substituted with up to four hydroxy, amino, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro or (C₁-C₄)alkoxy    optionally substituted with up to five fluoro.

A preferred group of compounds within Group F, designated Group FA, arethose compounds, prodrugs thereof and pharmaceutically acceptable saltsof said compounds or said prodrugs wherein:

-   R¹ is (R)-1-hydroxy-ethyl;-   R² is hydrogen;-   R³ is-   k is 0;-   Y¹ is a covalent bond; and-   R⁴³ is 4-pyrimidinyl substituted at the 2-position with    1-hydroxymethyl.

A preferred group of compounds within Group FA, designated Group FB, arethose compounds, prodrugs thereof and pharmaceutically acceptable saltsof said compounds or said prodrugs, which is1R-(4-{1′-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-[4,4]bipiperidinyl-1-yl}-pyrimidin-2-yl)-ethanol.

Another preferred group of compounds of formula I, designated Group G,are those compounds of formula I, prodrugs thereof and pharmaceuticallyacceptable salts of said compounds or said prodrugs, wherein:

-   R³ is-   R⁴² and R^(42a) are independently hydrogen, (C₃-C₇)cycloalkyl,    Ar⁶-(C₀-C₃)alkylenyl, Ar⁶—(C₂-C₄)alkenyl, Ar⁶-carbonyl or    (C₁-C₆)alkyl optionally substituted with up to five fluoro; and-   R⁴¹ and R^(41a) are independently hydrogen or (C₁-C₄)alkyl.

Still another preferred group of compounds of formula I, designatedGroup H, are those compounds of formula I, prodrugs thereof andpharmaceutically acceptable salts of said compounds or said prodrugs,wherein:

-   R¹ is C(OH)R⁴R⁵, where R⁴ and R⁵ are each independently hydrogen or    methyl;-   R² is hydrogen;-   R³ is-    wherein said R³ is substituted by R⁶, R⁷ or R⁸;-   G, G¹ and G² are taken separately and are each hydrogen and R⁶ is    hydrogen or (C₁-C₄)alkyl; R⁷ and R⁸ are each independently hydrogen    or (C₁-C₄)alkyl; or-   G and G¹ are taken together and are (C₁-C₃)alkylene and R⁶, R⁷, R⁸    and G² are hydrogen; or-   G¹ and G² are taken together and are (C₁-C₃) alkylene and R⁶, R⁷, R⁸    and G² are hydrogen;-   q is 0 or 1;-   X is a covalent bond, oxycarbonyl, vinylenylcarbonyl,    oxy(C₁-C₄)alkylenylcarbonyl, thio(C₁-C₄)alkylenylcarbonyl or    vinylenylsulfonyl; said vinylenylcarbonyl and said vinylenylsulfonyl    in the definition of X are optionally substituted on one or two    vinylenyl carbons with (C₁-C₄)alkyl, benzyl or Ar; said    oxy(C₁-C₄)alkylenylcarbonyl and said thio(C₁-C₄)alkylenylcarbonyl in    the definition of X are optionally substituted with up to two    (C₁-C₄)alkyl, benzyl or Ar;-   R⁹ is (C₃-C₇)cycloalkyl, Ar¹—(C₀-C₄)alkylenyl or (C₁-C₆)alkyl    optionally substituted with up to five fluoro;-   Ar¹ is phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,    triazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl,    phthalazinyl, cinnolinyl, naphthyridinyl, pteridinyl,    pyrazinopyrazinyl, pyrazinopyridazinyl, pyrimidopyridazinyl,    pyrimidopyrimidyl, pyridopyrimidyl, pyridopyrazinyl,    pyridopyridazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl,    thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl,    oxadiazolyl, thiadiazolyl, tetrazolyl, indolyl, benzofuranyl,    benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl,    indazolyl, benzisoxazolyl, benzisothiazolyl, pyrrolopyridyl,    furopyridyl, thienopyridyl, imidazolopyridyl, oxazolopyridyl,    thiazolopyridyl, pyrazolopyridyl, isoxazolopyridyl,    isothiazolopyridyl, pyrrolopyrimidyl, furopyrimidyl,    thienopyrimidyl, imidazolopyrimidyl, oxazolopyrimidyl,    thiazolopyrimidyl, pyrazolopyrimidyl, isoxazolopyrimidyl,    isothiazolopyrimidyl, pyrrolopyrazinyl, furopyrazinyl,    thienopyrazinyl, imidazolopyrazinyl, oxazolopyrazinyl,    thiazolopyrazinyl, pyrazolopyrazinyl, isoxazolopyrazinyl,    isothiazolopyrazinyl, pyrrolopyridazinyl, furopyridazinyl,    thienopyridazinyl, imidazolopyridazinyl, oxazolopyridazinyl,    thiazolopyridazinyl, pyrazolopyridazinyl, isoxazolopyridazinyl or    isothiazolopyridazinyl; and-   said Ar¹ is optionally substituted as set forth above.

A preferred group of compounds within Group H, designated Group HA, arethose compounds, prodrugs thereof and pharmaceutically acceptable saltsof said compounds or said prodrugs, wherein:

-   X is a covalent bond, oxycarbonyl or vinylenylcarbonyl optionally    substituted on one or two vinylenyl carbons with (C₁-C₄)alkyl,    benzyl or Ar;-   R⁹ is Ar¹—(C₀-C₄)alkylenyl;-   Ar¹ is phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, triazinyl,    quinolyl, isoquinolyl, quinazolyl, quinoxalyl, furanyl, thienyl,    indolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl,    furopyridyl, oxazolopyridyl, thiazolopyridyl, thienopyridyl,    furopyrimidyl, thienopyrimidyl, oxazolopyrimidyl or    thiazolopyrimidyl; and said Ar¹ is optionally substituted as set    forth in claim 1.

A preferred group of compounds within Group HA, designated Group HB, arethose compounds, prodrugs thereof and pharmaceutically acceptable saltsof said compounds or said prodrugs, wherein:

-   R² is hydrogen;-   R⁴ is hydrogen or methyl;-   R⁵ is methyl;-   G, G¹ and G² are hydrogen;-   R⁶ and R⁷ are each independently hydrogen or methyl;-   R⁸ is hydrogen.

A preferred group of compounds within Group HB, designated Group HC, arethose compounds, prodrugs thereof and pharmaceutically acceptable saltsof said compounds or said prodrugs wherein:

-   R¹ is (R)-1-hydroxy-ethyl; and-   R³ is

A preferred compound within Group HC is the compound wherein R⁹ is2-furo[3,2-c]pyridyl, a prodrug thereof or a pharmaceutically acceptablesalt of said compound or said prodrug.

Another preferred compound within Group HC is the compound wherein R⁹ is2-(4-chloro-furo[3,2-c]pyridyl), a prodrug thereof or a pharmaceuticallyacceptable salt of said compound, or said prodrug.

Another preferred compound within Group HC is the compound wherein R⁹ is2-(4-pyrrolidin-1-yl-furo[3,2-c]pyridyl), a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within Group HC is the compound wherein R⁹ is2-(4-morpholin-4-yl-furo[3,2-c]pyridyl), a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within Group HC is the compound wherein R⁹ is2-imidazo[1,2-a]pyridyl, a prodrug thereof or a pharmaceuticallyacceptable salt of said compound or said prodrug.

Preferred compounds within Group HC arefuro[3,2-c]pyridin-2-yl-4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-methanone;(4-chloro-furo[3,2-c]pyridin-2-yl)-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-methanone;{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-(4-pyrrolidin-1-yl-furo[3,2-c]pyridin-2-yl)-methanone;{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl(4-morpholin-4-yl-furo[3,2-c]pyridin-2-yl)-methanone;and{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-imidazo[1,2-a]pyridin-2-yl-methanone.

Another preferred group of compounds within Group HB, designated GroupHD, are those compounds, prodrugs thereof and pharmaceuticallyacceptable salts of said compounds or said prodrugs wherein:

-   R¹ is (R)-1-hydroxy-ethyl; and-   R³ is

A preferred compound within Group HD is the compound wherein R⁹ is 2furo[3,2-c]pyridyl, a prodrug thereof or a pharmaceutically acceptablesalt of said compound or said prodrug.

An especially preferred compound within Group HD isfuro[3,2-c]pyridin-2-yl-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-methanone.

Another preferred group of compounds within Group HB, designated GroupHE, are those compounds, prodrugs thereof and pharmaceuticallyacceptable salts of said compounds or said prodrugs wherein:

-   R¹ is (R)-1-hydroxy-ethyl; and-   R³ is

A preferred compound within Group HE is the compound wherein R⁹ is3-pyridyl, a prodrug thereof or a pharmaceutically acceptable salt ofsaid compound or said prodrug.

Another preferred compound within Group HE is the compound wherein R⁹ is3-(2-methylpyridyl), a prodrug thereof or a pharmaceutically acceptablesalt of said compound or said prodrug.

Another preferred compound within Group HE is the compound wherein R⁹ is3-(5-chloropyridyl), a prodrug thereof or a pharmaceutically acceptablesalt of said compound or said prodrug.

Another preferred compound within Group HE is the compound wherein R⁹ is3-(6-methylpyridyl), a prodrug thereof or a pharmaceutically acceptablesalt of said compound or said prodrug.

Preferred compounds within Group HE are4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carboxylicacid pyridin-3-yl ester;4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carboxylicacid 2-methyl-pyridin-3-yl ester;4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carboxylicacid 5-chloro-pyridin-3-yl ester; and4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carboxylicacid 6-methyl-pyridin-3-yl ester.

Another preferred group of compounds within Group HB, designated GroupHF, are those compounds, prodrugs thereof and pharmaceuticallyacceptable salts of said compounds or said prodrugs wherein:

-   R¹ is (R)-1-hydroxy-ethyl; and-   R³ is

A preferred compound within the Group HF is the compound wherein R⁹ is2-thienyl, a prodrug thereof or a pharmaceutically acceptable salt ofsaid compound or said prodrug.

An especially preferred compound within Group HF is(E)-1{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-3-thiophen-2-yl-propenone.

Another preferred group of compounds within Group HB, designated GroupHG, are those compounds, prodrugs thereof and pharmaceuticallyacceptable salts of said compounds or said prodrugs wherein:

-   R¹ is (R)-1-hydroxy-ethyl;-   R³ is-   R⁹ is pyrimidyl or triazinyl; said pyrimidyl or triazinyl is    optionally substituted with up to two hydroxy, (C₁-C₄)alkyl,    (C₃-C₇)cycloalkyl, (C₁-C₄)alkoxy, hydroxy-(C₁-C₄)alkyl,    (C₄-C₄)alkoxy-(C₁-C₄)alkylenyl, phenyl, piperazinyl optionally    substituted with (C₁-C₄)alkyl, or imidazolyl optionally substituted    with up to two (C₁-C₄)alkyl.

A preferred group of compounds within Group HG, designated Group HH, arethose compounds, prodrugs thereof and pharmaceutically acceptable saltsof said compounds or said prodrugs wherein: R⁹ is pyrimid-2-yloptionally substituted with up to two (C₁-C₄)alkyl, hydroxy-(C₁-C₄)alkylor (C₁-C₄)alkoxy-(C₁-C₄)alkyl.

A preferred compound within the Group HH is the compound wherein R⁹ is4,6-dimethylpyrimid-2-yl, a prodrug thereof or a pharmaceuticallyacceptable salt of said compound or said prodrug.

Another preferred compound within the Group HH is the compound whereinR⁹ is 4-methoxymethyl-6-methylpyrimid-2-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HH is the compound whereinR⁹ is 4-hydroxymethyl-6-methylpyrimid-2-yl, a prodrug thereof or apharmaceutically, acceptable salt of said compound or said prodrug.

A preferred group of compounds within the Group HH are1R-{4-[4-(4,6-dimethyl-pyrimidin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R{4-[4-(4-methoxymethyl-6-methyl-pyrimidin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;and1R-{4-[4-(4-hydroxymethyl-6-methyl-pyrimidin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}ethanol.

Another preferred group of compounds within the Group HG, designated HI,are those compounds, prodrugs thereof and pharmaceutically acceptablesalts of said compounds or said prodrugs wherein: R⁹ is pyrimid-4-yloptionally substituted with up to two (C₁-C₄)alkylpiperazin-1-yl orimidazolyl; and said imidazolyl is optionally substituted with up to two(C₁-C₄)alkyl.

A preferred compound within the Group HI is the compound wherein R⁹ is2-(4-methylpiperazin-1-yl)-pyrimid-4-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HI is the compound whereinR⁹ is 2-(4-ethylpiperazin-1-yl) pyrimid-4-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound, within the Group HI is the compound whereinR⁹ is 2-(4-methylimidazol-1-yl) pyrimid-4-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrugwherein.

Another preferred compound within the Group HI is the compound whereinR⁹ is 2-(2-methylimidazol-1-yl) pyrimid-4-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrugwherein.

Another preferred compound within the Group HI is the compound whereinR⁹ is 2-(2,4-dimethylimidazol-1-yl) pyrimid-4-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HI is the compound whereinR⁹ is 2-(4-isopropyl piperazin-1-yl) pyrimid-4-yl, a prodrug thereof ora pharmaceutically acceptable salt of said compound or said prodrug.

Preferred compounds within Group HI are1R-(4-{3R,5S-dimethyl-4-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;1R-(44-[2-(4-ethyl-piperazin-1-yl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl)pyrimidin-2-yl)-ethanol;1R-(43R,5S-dimethyl-4-[2-(4-methyl-imidazol-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;1R-(4-{3R,5S-dimethyl-4-[2-(2-methyl-imidazol-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;1R-(4-{4-[2-(2,4-dimethyl-imidazol-1-yl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yliethanol; and1R-(4-{4-[2-(4-isopropyl-piperazin-1-yl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol.

Another preferred group of compounds within Group HG, designated GroupHJ, are those compounds, prodrugs thereof and pharmaceuticallyacceptable salts of said compounds or said prodrugs wherein: R⁹ is[1,3,5]-triazin-2-yl optionally substituted with up to two hydroxy,(C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₄)alkoxy, hydroxy-(C₁-C₄)alkyl,(C₁-C₄)alkylpiperazin-1-yl or phenyl.

A preferred compound within the Group HJ is the compound wherein R⁹ is4-methyl-6-(4-methylpiperazin-1-yl)-[1,3,5]-triazin-2-yl, a prodrugthereof or a pharmaceutically acceptable salt of said compound or saidprodrug.

Another preferred compound within the Group HJ is the compound whereinR⁹ is 4-methoxy-6-methyl-[1,3,5]-triazin-2-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HJ is the compound whereinR⁹ is 4,6-dimethyoxy-[1,3,5]-triazin-2-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HJ is the compound wherein,R⁹ is 4-ethoxy-6-methyl-[1,3,5]-triazin-2-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HJ is the compound whereinR⁹ is 4-isopropoxy-6-methyl-[1,3,5]-triazin-2-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HJ is the compound whereinR⁹ is 4-phenyl-[1,3,5]-triazin-2-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HJ is the compound whereinR⁹ is 4-hydroxymethyl-6-methoxy-[1,3,5]-triazin-2-yl, a prodrug thereofor a pharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HJ is the compound wherein.R⁹ is 4-isopropoxy-6-methoxy-[1,3,5]-triazin-2-yl, a prod rug thereof ora pharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HJ is the compound whereinR⁹ is 4-isopropyl-[1,3,5]-triazin-2-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HJ is the compound whereinR⁹ is 4-ethyl-6-methoxy-[1,3,5]-triazin-2-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HJ is the compound whereinR⁹ is 4-cyclopropyl-[1,3,5]-triazin-2-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HJ is the compound whereinR⁹ is 4,6-dimethyl-[1,3,5]-triazin-2-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HJ is the compound whereinR⁹ is 4-methyl-6-phenyl-[1,3,5]-triazin-2-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Preferred compounds within the Group HJ are,1R-(43R,5S-dimethyl-[4-methyl-6-(4-methyl-piperazin-1-yl)-[1,3,5]triazin-2-yl]-piperazin-1-yl}-pyrmidin-2-yl)-ethanol;1R-{4-[4-(4-methoxy-6-methyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[4-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[4-(4-ethoxy-6-methyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1,yl]-pyrimidin-2-yl}-ethanol;1R-{4-[4-(4-isopropoxy-6-methyl-[1,3,5]triazin2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[3R,5S-dimethyl-4-(4-phenyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[4-(4-hydroxymethyl-6-methoxy-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]pyrimidin-2-yl}-ethanol;1R-{4-[4-(4-isopropoxy-6-methoxy-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[4-(4-isopropyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl})ethanol;1R-{4-[4-(4,6-dimethyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[3R,5S-dimethyl-4-(4-methyl-6-phenyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]pyrimidin-2-yl}-ethanol;1R{4-[4-(4-cyclopropyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}thanol;and1R{4-[4-(4-ethyl-6-methoxy-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}ethanol.

Another group of preferred compounds within the Group HB, designatedGroup HK, are those, compounds, prodrugs thereof and pharmaceuticallyacceptable salts, of said compounds or said prodrugs wherein:

-   R¹ is (R)-1-hydroxy-ethyl;-   R³ is-   R⁹ is pyrimidyl or triazinyl, said pyrimidyl and triazinyl    optionally substituted with up to two hydroxy, (C₁-C₄)alkyl,    (C₃-C₇)cycloalkyl, (C₁-C₄)alkoxy, hydroxy-(C₁-C₄)alkyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, triazolyl, acetyl, morpholinyl,    (C₁-C₄)alkylpiperazinyl, phenyl or imidazolyl optionally substituted    with up to two (C₁-C₄)alkyl.

A preferred group of compounds within the Group HK, designated HL, arethose compounds, prodrugs thereof and pharmaceutically acceptable saltsof said compounds or said prodrugs wherein: R⁹ is pyrimid-2-yloptionally substituted with up to two (C₁-C₄)alkyl, hydroxy-(C₁-C₄)alkylor triazolyl.

A preferred compound within the Group HL is the compound wherein R⁹ is4,6-dimethyl-pyrimid-2-yl, a prodrug thereof or a pharmaceuticallyacceptable salt of said compound or said prodrug.

Another preferred compound within the Group HL is the compound whereinR⁹ is 4-hydroxymethyl-6-methylpyrimid-2-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HL is the compound whereinR⁹ is 4-[1,2,4]-triazol-1-yl-pyrimid-2-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Preferred compounds within the Group HL are1R{4-[4-(4,6-dimethyl-pyrimidin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{47[4-(4-hydroxymethyl-6-methyl-pyrimidin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}ethanol; and1R-{4-[2R,6S-dimethyl-4-(4-[1,2,4]triazol-1-yl-pyrimidin-2-yl)-piperazin-11-yl]-pyrimidin-2-yl}thanol.

Another preferred group of compounds within the Group HK, designatedGroup HM, are those compounds, prodrugs thereof and pharmaceuticallyacceptable salts of said compounds or said prodrugs wherein: R⁹ ispyrimid-4-yl optionally substituted with up to two (C₁-C₄)alkyl,hydroxy-(C₁-C₄)alkyl, acetyl, morpholinyl, (C₁-C₄)alkylpiperazinyl,triazolyl or imidazolyl optionally substituted with up to two(C₁-C₄)alkyl.

A preferred compound within the Group HM is the compound wherein R⁹ is2,6-dimethyl-pyrimid-4-yl, a prodrug thereof or a pharmaceuticallyacceptable salt of said compound or said prodrug.

Another preferred compound within the Group HM is the compound whereinR⁹ is 2-hydroxymethyl-6-methyl-pyrimid-4-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HM is the compound whereinR⁹ is 2-acetyl-pyrimid-4-yl, a prodrug thereof or a pharmaceuticallyacceptable salt of said compound or said prodrug.

Another preferred compound within the Group HM is the compound whereinR⁹ is 2-morpholin-4-yl-pyrimid-4-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HM is the compound whereinR⁹ is 2-(4-methylpiperazin-1-yl)-pyrimid-4-yl; a prodrug thereof or apharmaceutically acceptable skit of said compound or said prodrug.

Another preferred compound within the Group HM is the compound whereinR⁹ is 2-[1,2,4]-triazol-1-yl)-pyrimid-4-yl, a prodrug thereof or apharmaceutically acceptable, salt of said compound or said prodrug.

Another preferred compound within the Group HM is the compound whereinR⁹ is 2-(1S-hydroxyethyl)-pyrimid-4-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HM is the compound whereinR⁹ is 2-(1R-hydroxyethyl)-pyrimid-4-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HM is the compound whereinR⁹ is 2-(4-ethylpiperazin-1-yl)-pyrimid-4-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HM is the compound whereinR⁹ is 2-(4-methylimidazol-1-yl)-pyrimid-4-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HM is the compound whereinR⁹ is 2-(2,4-dimethylimidazol-1-yl)-pyrimid-4-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Preferred compounds within the HB Group are1R-{4-[4-(2,6-dimethyl-pyrimidin-4-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;1R-{4-[4-(2-hydroxymethyl-6-methyl-pyrimidin-4-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-(4-{4-[2-(1S-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanone;1R-{4-[2R,6S-dimethyl-4-(2-morpholin-4-yl-pyrimidin-4-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-(4-{2R,6S-dimethyl-4-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}pyrimidin-2-yl)ethanol;1R-{4-[2R,6S-dimethyl-4-(2-[1,2,4]triazol-1-yl-pyrimidin-4-yl)-piperazin-1-yl]-pyrimidin-2-yl}ethanol;1R-(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6R-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;1R-(4-{4-[2-(4-ethyl-piperazin-1-yl)-pyrimidinyl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;1R-(4-{2R,6S-dimethyl-4-[2-(4-methyl-imidazol-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol,and1R-(4-{4-[2-(2,4-dimethyl-imidazol-1-yl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol.

Another preferred compound within the Group HB is the compound wherein,R¹ is (R)-1-hydroxyethyl; R³ is

R⁹ is 2-(1R-hydroxyethyl-pyrimid-4-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

A preferred group of compounds within the Group HK, designated Group HN,are those compounds, prodrugs thereof and pharmaceutically acceptablesalts of said compounds and said prodrugs, wherein R⁹ is[1,3,5]-triazin-2-yl optionally substituted with up to two hydroxy,(C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, hydroxy-(C₁—; C₄)alkyl,(C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy, morpholinyl or phenyl.

A preferred compound within the Group HN is the compound wherein R⁹ is4-morpholin-4-yl-[1,3,5]-triazin-2-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HN is the compound whereinR⁹ is 4-methoxy-6-methyl-[1,3,5]-triazin-2-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HN is the compound whereinR⁹ is 4,6-dimethoxy-[1,3,5]-triazin-2-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HN is the compound whereinR⁹ is 4-phenyl-[1,3,5]-triazin-2-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HN is the compound whereinR⁹ is 4-cyclopropyl-[1,3,5]-triazin-2-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HN is the compound whereinR⁹ is 4,6-dimethyl-[1,3,5]-triazin-2-yl, a prodrug, thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HN is the compound whereinR⁹ is 4-hydroxymethyl-6-phenyl-[1,3,5]-triazin-2-yl, a, prodrug thereofor a pharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HN is the compound whereinR⁹ is 4-methoxy-6-methoxymethyl-[1,3,5]-triazin-2-yl, a prodrug thereofor a pharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HN is the compound whereinR⁹ is 4-methyl-[1,3,5]-triazin-2-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HN is the compound whereinR⁹ is 4-methoxymethyl-6-phenyl-[1,3,5]triazin-2-yl, a prodrug thereof ora pharmaceutically acceptable salt of said compound or said prodrug.

Preferred compounds within the Group HN are1R-{4-[2R,6S-dimethyl-4-(4-morpholin-4-yl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R{4-[4-(4-methoxy-6-methyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}ethanol;1R-{4-[4-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[4-(4-cyclopropyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[4-(4,6-dimethyl-[1,3,5]triazin-2-yl)2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[4-(4-hydroxymethyl-6-phenyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[4-(4-methoxy-6-methoxymethyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[2R,6S-dimethyl-4-(4-methyl-[1,3,5]triazin-2-yl)piperazin-1-yl]-pyrimidin-2-yl-ethanol;1R-{4-[4-(4-methoxymethyl-6-phenyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;and1R-[4-[2R,6S-dimethyl-4-(4-phenyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.

Another preferred group of compounds within the Group HB, designatedGroup HO, are those compounds, prodrugs thereof and pharmaceuticallyacceptable salts of said compounds or said prodrugs wherein:

-   R¹ is (R)-1-hydroxy-ethyl;-   R³ is-   R⁹ is pyrimidyl, quinoxalyl or oxazolopyridyl optionally substituted    with up to two (C₁-C₄)alkyl, (C₁-C₄)alkoxy or hydroxy-(C₁-C₄)alkyl.

A preferred compound within the Group HO is the compound wherein R⁹ is4-hydroxymethyl-6-methyl-pyrimid-2-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HO is the compound whereinR⁹ is 2-hydroxymethyl-pyrimid-4-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HO is the compound whereinR⁹ is 2-hydroxymethyl-6-methyl-pyrimid-4-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Another preferred compound within the Group HO is the compound wherein,R⁹ is 2-(oxazolo[5,4-b]pyridyl) a prodrug thereof or a pharmaceuticallyacceptable salt of said compound or said prodrug.

Another preferred compound within the Group HO is the compound whereinR⁹ is 2-(oxazolo[4,5-b]pyridyl, a prodrug thereof or a pharmaceuticallyacceptable salt of said compound or said prodrug.

Another preferred compound within the Group HO is the compound whereinR⁹ is 2-quinoxalyl, a prodrug thereof or a pharmaceutically acceptablesalt of said compound or said prodrug.

Preferred compounds within the Group HO are1R-{4-[4-(4-hydroxymethyl-6-methyl-pyrimidin-2-yl)-3S-methyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[4-(2-hydroxymethyl-pyrimidin-4-yl)-3S-methyl-piperazin-1-yl]-pyrimidin-2-yl}thanol;1R-{4-[4-(2-hydroxymethyl-6-methyl-pyrimidin-4-yl)-3S-methyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-[4-(3S-methyl-4-oxazolo[5,4-b]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethanol;1R-[4-(3S-methyl-4-oxazolo[4,5-b]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethanol;and1R-[4-(3S-methyl-4-quinoxalin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethanol.

Another preferred group of compounds within the Group HB, designatedGroup HP, are those compounds, prodrugs thereof and pharmaceuticallyacceptable salts of said compounds or said prodrugs, wherein:

-   R¹ is (R)-1-hydroxy-ethyl;-   R³ is-   R⁹ is pyrimidyl optionally substituted with up to two (C₁-C₄)alkyl,    (C₁-C₄)alkoxy, hydroxy-(C₁-C₄)alkyl.

A preferred compound within the Group, HP is the compound wherein R⁹ is2-(1R-hydroxyethyl)-pyrimid-4-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

A preferred compound within the Group HP is1R-(4-{4-[2-(1R-hydroxy-ethyl)pyrimidin-4-yl]-2R-methyl-piperazin-1-yl}pyrimidin-2-yl)-ethanol.

Another preferred group of compounds within the Group HB, designated HQ,are those compounds, prodrugs thereof and pharmaceutically acceptablesalts of said compounds or said prodrugs wherein:

-   R¹ is (R)-1-hydroxy-ethyl;-   R³ is-   R⁹ is pyrimidyl optionally substituted with up to two (C₁-C₄)alkyl,    (C₁-C₄)alkoxy, hydroxy-(C₁-C₄)alkyl.

A preferred compound within the Group HO is the compound wherein R⁹ is2-(1R-hydroxyethyl)-pyrimid-4-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

An especially preferred compound within the Group HQ is(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol.

Another preferred group of compounds within the Group HB, designatedGroup HR, are those compounds, prodrugs thereof and pharmaceuticallyacceptable salts of said compounds or said prodrugs wherein:

-   R¹ is (S)-1-hydroxy-ethyl;-   R³ is-   R⁹ is pyrimidyl optionally substituted with up to two (C₁-C₄)alkyl,    (C₁-C₄)alkoxy or hydroxy-(C₁-C₄)alkyl.

A preferred compound within the Group HR is the compound wherein R⁹ is2-(1R-hydroxy-ethyl)-pyrimid-4-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

An especially preferred compound within the Group HR is 1S-(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol.

Yet another preferred group of compounds within the Group HB, designatedGroup HS, are those compounds, prodrugs thereof and pharmaceuticallyacceptable salts of said compounds or said prodrugs wherein:

-   R¹ is acetyl;-   R³ is-   R⁹ is pyrimidyl optionally substituted with up to two (C₁-C₄)alkyl,    (C₁-C₄)alkoxy, acetyl or hydroxy-(C₁-C₄)alkyl.

A preferred compound within the Group HS is the compound wherein R⁹ is2-acetyl-pyrimid-4-yl, a prodrug thereof or a pharmaceuticallyacceptable salt of said compound or said prodrug.

A preferred compound within the Group HS is the compound wherein R⁹ is2-(1R-hydroxyethyl)-pyrimid-4-yl, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

Especially preferred compounds within the Group HS are1-{4-[4-(2-acetyl-pyrimidin-4-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanoneor1-(4{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)ethanone.

A pharmaceutical composition, designated Composition A, comprising acompound of formula I, a prodrug thereof or a, pharmaceuticallyacceptable salt of said compound or said prodrug and a pharmaceuticallyacceptable carrier or diluent.

A method of inhibiting sorbitol dehydrogenase in a mammal in need ofsuch inhibition comprising administering to said mammal a sorbitoldehydrogenase inhibiting amount of a compound of formula I, a prodrugthereof or a pharmaceutically acceptable salt of said compound or saidprodrug.

A method of treating diabetes in a mammal suffering from diabetescomprising administering to said mammal an effective amount of acompound of formula I, a prodrug thereof or a pharmaceuticallyacceptable salt of said compound or said prodrug.

A method, designated Method A, of treating or preventing diabeticcomplications in a mammal comprising administering to said mammal aneffective amount of a compound of formula I, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug.

A method of Method A wherein said mammal is suffering from diabetes.

A method of Method A wherein said diabetic complication is diabeticneuropathy.

A method of Method A wherein said diabetic complication is diabeticnephropathy.

A method of Method A wherein said diabetic complication is diabeticretinopathy.

A method of Method A wherein said diabetic complication is foot ulcers.

A method of Method A wherein said diabetic complication is acardiovascular condition.

A pharmaceutical composition, designated Composition B, comprising acompound of formula I, a prodrug thereof or a pharmaceuticallyacceptable salt of said compound or said prodrug and an aldose reductaseinhibitor, a prodrug, thereof or a pharmaceutically acceptable salt ofsaid aldose reductase inhibitor or, said prodrug.

A composition of Composition B additionally comprising apharmaceutically acceptable carrier or diluent.

A method of treating diabetes in a mammal suffering from diabetescomprising administering to said mammal an effective amount of acompound of formula I, a prodrug thereof or a pharmaceuticallyacceptable salt of said compound or said prodrug and an aldose reductaseinhibitor, a prodrug of said aldose reductase inhibitor or apharmaceutically acceptable salt of said aldose reductase inhibitor orsaid prodrug.

A method, designated Method B, of treating or preventing diabeticcomplications in a mammal comprising administering to said mammal aneffective amount of a compound of formula I, a prodrug thereof or apharmaceutically acceptable of said compound or said prodrug and analdose reductase inhibitor, a prodrug of said aldose reductase inhibitoror a pharmaceutically acceptable salt of said aldose reductase inhibitoror said prodrug thereof.

A method of Method B wherein said mammal is suffering from diabetes.

A method of Method B wherein said diabetic complication is diabeticneuropathy.

A method of Method B wherein said diabetic complication is diabeticnephropathy.

A method of Method B wherein said diabetic complication is diabeticretinopathy.

A method of Method B wherein said diabetic complication is foot ulcers.

A method of Method B wherein said diabetic complication is acardiovascular condition.

A pharmaceutical composition, designated Composition C, comprising acompound of formula I, a prodrug thereof or a pharmaceuticallyacceptable salt of said compound or said prodrug and a sodium hydrogenion exchange (NHE-1) inhibitor, a prodrug of said NHE-1 inhibitor or apharmaceutically acceptable salt of said NHE-1 inhibitor or said prodrugthereof.

A method, designated Method C, of treating ischemia in a mammalsuffering from ischemia comprising administering to said mammal aneffective amount of a compound of claim 1, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug and asodium hydrogen ion exchange (NHE-1) inhibitor, a prodrug of said NHE-1inhibitor or a pharmaceutically acceptable salt of said NHE-1 inhibitoror said prodrug.

A method of Method C wherein said ischemia is perioperative myocardialischemia.

A method of treating or preventing diabetic complications in a mammal,designated Method D, comprising administering to said mammal aneffective amount of a compound of formula I, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug and asodium hydrogen ion exchange (NHE-1) inhibitor, a prodrug of said NHE-1inhibitor or a pharmaceutically acceptable salt of said NHE-1 inhibitoror said prodrug.

A method of Method D wherein said mammal is suffering from diabetes.

A method of Method D wherein said diabetic complication is diabeticneuropathy.

A method of Method D wherein said diabetic complication is diabeticnephropathy.

A method of Method D wherein said diabetic complication is diabeticretinopathy.

A method of Method D wherein said diabetic complication is foot ulcers.

A method of Method D wherein said diabetic complication is acardiovascular condition.

A method of treating diabetes in a mammal suffering from diabetescomprising administering to said mammal an effective amount of acompound of formula I, a prodrug thereof or a pharmaceuticallyacceptable salt of said compound or said prodrug, and a sodium hydrogenion exchange (NHE-1) inhibitor, a prodrug of said NHE-1 inhibitor or apharmaceutically acceptable salt of said NHE-1 inhibitor or saidprodrug.

A kit comprising:

-   -   a. a compound of formula I, a prodrug thereof or a        pharmaceutically acceptable salt of said compound or said        prodrug in a first unit dosage form;    -   b. an aldose reductase inhibitor, a prodrug thereof or a        pharmaceutically acceptable salt of said prodrug or said aldose        reductase inhibitor in a second unit dosage form; and    -   c. a container.

A kit comprising:

-   -   a. a compound of formula I, a prodrug thereof or a        pharmaceutically acceptable salt of said compound or said        prodrug in a first unit dosage form;    -   b. a sodium hydrogen ion exchange (NHE-1) inhibitor, a prodrug        thereof or a pharmaceutically acceptable salt of said prodrug or        said NHE-1 inhibitor in a second unit dosage form; and    -   c. a container.

A method, designated Method E, of inhibiting sorbitol dehydrogenase in amammal in need thereof comprising administering to said mammalComposition A.

A method of Method E wherein said ischemia is perioperative myocardial,ischemia.

A method of treating ischemia in a mammal suffering from ischemiacomprising administering to said mammal Composition C.

A method, designated Method F, of treating or preventing diabeticcomplications in a mammal comprising administering to said mammalComposition A.

A method of Method F wherein said mammal is suffering from diabetes.

A method, designated Method G, of treating or preventing diabeticcomplications in a mammal comprising administering to said mammalComposition B.

A method of Method G wherein said mammal is suffering from diabetes.

A method, designated Method H, of treating or preventing diabeticcomplications in a mammal comprising administering to said mammalComposition C.

A method of Method H wherein said mammal is suffering from diabetes.

A compound of formula I, a prodrug thereof or a pharmaceuticallyacceptable salt of said compound or said prodrug, wherein:

-   RX is C(OH)R⁴R⁵, where R⁴ and R⁵ are each independently hydrogen or    methyl;-   R² is hydrogen;-   R³ is-    wherein said piperazinyl R³ is substituted by R⁶, R⁷ or R⁸;-   G, G¹ and G² are taken separately and are each hydrogen and R⁶ is    hydrogen or (C₁-C₄)alkyl; R⁷ and R⁸, are each independently hydrogen    or (C₁-C₄)alkyl; or-   G and G¹ are taken together and are (C₁-C₃)alkylene and R⁶, R⁷, R⁸    and G² are hydrogen; or-   G¹ and G² are taken together and are (C₁-C₃)alkylene and R⁶, R⁷, R⁸    and G are hydrogen;-   q is 0 or 1;-   X is a covalent bond, oxycarbonyl, vinylenylcarbonyl,    oxy(C₁-C₄)alkylenylcarbonyl, thio(C₁-C₄)alkylenylcarbonyl or    vinylenylsulfonyl; said vinylenylcarbonyl and said vinylenylsulfonyl    in the definition of X are optionally substituted on one or two    vinylenyl carbons with (C₁-C₄)alkyl, benzyl or Ar; said    oxy(C₁-C₄)alkylenylcarbonyl and said thio(C₁-C₄)alkylenylcarbonyl in    the definition of X are optionally substituted with up to two    (C₁-C₄)alkyl, benzyl or Ar;-   R⁹ is (C₃-C₇)cycloalkyl, Ar¹—(C₀-C₄)alkylenyl or (C₁-C₆)alkyl    optionally substituted with up to five fluoro;-   Ar¹ is phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,    triazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl,    phthalazinyl, cinnolinyl, naphthyridinyl, pteridinyl,    pyrazinopyrazinyl, pyrazinopyridazinyl, pyrimidopyridazinyl,    pyrimidopyrimidyl, pyridopyrimidyl, pyridopyrazinyl,    pyridopyridazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl,    thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl,    oxadiazolyl, thiadiazolyl, tetrazolyl, indolyl, benzofuranyl,    benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl,    indazolyl, benzisoxazolyl, benzisothiazolyl, pyrrolopyridyl,    furopyridyl, thienopyridyl, imidazolopyridyl, oxazolopyridyl,    thiazolopyridyl, pyrazolopyridyl, isoxazolopyridyl,    isothiazolopyridyl, pyrrolopyrimidyl, furopyrimidyl,    thienopyrimidyl, imidazolopyrimidyl, oxazolopyrimidyl,    thiazolopyrimidyl, pyrazolopyrimidyl, isoxazolopyrimidyl,    isothiazolopyrimidyl, pyrrolopyrazinyl, furopyrazinyl,    thienopyrazinyl, imidazolopyrazinyl, oxazolopyrazinyl,    thiazolopyrazinyl, pyrazolopyrazinyl, isoxazolopyrazinyl,    isothiazolopyrazinyl, pyrrolopyridazinyl, furopyridazinyl,    thienopyridazinyl, imidazolopyridazinyl, oxazolopyridazinyl,    thiazolopyridazinyl, pyrazolopyridazinyl, isoxazolopyridazinyl or    isothiazolopyridazinyl; and-   said Ar¹ is optionally substituted as set forth above;-   k is 0, 1, 2, 3 or 4;-   Y¹ is a covalent bond, carbonyl, sulfonyl or oxycarbonyl;-   R⁴³ is (C₃-C₇)cycloalkyl, Ar⁵—(C₀-C₄)alkylenyl, NR⁴⁷R48 or    (C₁-C₆)alkyl optionally substituted with one to five fluoro;    provided that when Y¹ is a covalent bond or oxycarbonyl, then R⁴³ is    not NR⁴⁷R⁴⁸;-   R⁴⁷ and R⁴⁸ are taken separately and are each independently selected    from hydrogen, Ar⁵, (C₁-C₆)alkyl and Ar⁵—(C₀-C₄)alkylenyl; or-   R⁴⁷ and R⁴⁸ are taken together with the nitrogen atom to which they    are attached to form azetidinyl, pyrrolidinyl, piperidinyl,    piperazinyl, morpholinyl, azepinyl, azabicyclo[3.2.2]nonanyl,    azabicyclo[2.2.1]heptyl, 1,2,3,4-tetrahydroisoquinolyl,    6,7-dihydro-5H-dibenzo[c,e]azepinyl or    5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl; said azetidinyl in the    definition of R⁴⁷ and R⁴⁸ are optionally substituted with one    hydroxy, amino, hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl,    (C₁-C₄)alkyl optionally substituted with up to five fluoro or    (C₁-C₄)alkoxy optionally substituted with up to five fluoro; said    pyrrolidinyl, piperidinyl and azepinyl in the definition of R⁴⁷ and    R⁴ are optionally substituted with up to two hydroxy, amino,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro or (C₁-C₄)alkoxy    optionally substituted with up to five fluoro; said morpholinyl in    the definition of R⁴⁷ and R⁴⁸ is optionally substituted with up to    two substituents independently selected from hydroxy-(C₁-C₄)alkyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally substituted with    up to five fluoro and (C₁-C₄)alkoxy optionally substituted with up    to five fluoro; said piperazinyl, 1,2,3,4-tetrahydroisoquinolyl and    5,6,7,8-tetrahydro[4,3-d]pyrimidyl in the definition of R⁴⁷ and R⁴    are optionally substituted with up to three hydroxy, amino, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro or (Cl-t4)alkoxy    optionally substituted with up to five fluoro; and said    6,7-dihydro-5H-dibenzo[c,e]azepinyl in the definition of R⁴⁷ and R⁴⁸    are optionally substituted with up to four hydroxy, amino, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro or (C₁-C₄alkoxy    optionally substituted with up to five fluoro;-   Ar⁵ is independently defined as set forth for Ar and Ar¹ above;-   Ar⁵ is optionally independently substituted as set forth for Ar and    Ar¹ above.

A compound selected from1R-(4-{1′-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-[4,4]bipiperidinyl-1-yl}-pyrimidin-2-yl)-ethanol;furo[3,2-c]pyridin-2-yl-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-methanone;(4-chloro-furo[3,2-c]pyridin-2-yl)-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-methanone;{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-(4-pyrrolidin-1-yl-furo[3,2-c]pyridin-2-yl)-methanone;{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}(4-morpholin-4-yl-furo[3,2-c]pyridin-2-yl)-methanone;{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-imidazo[1,2-a]pyridin-2-yl-methanone;furo[3,2-c]pyridin-2-yl-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-methanone;4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carboxylicacid pyridin-3-yl ester,4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carboxylicacid 2-methyl-pyridin-3-yl ester;4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carboxylicacid 5-chloro-pyridin-3-yl ester;4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carboxylicacid 6-methyl-pyridin-3-yl ester;(E)-1-(4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl)₃-thiophen-2-yl-propenone;1R-{4-[4-(4,6-dimethyl-pyrimidin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[4-(4-methoxymethyl-6-methyl-pyrimidin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}ethanol;1R-{4-[4-(4-hydroxymethyl-6-methyl-pyrimidin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-(4-{3R,5S-dimethyl-4-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;1R-(4-{4-[2-(4-ethyl-piperazin-1-yl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;1R-(4-{3R,5S-dimethyl-4-[2-(4-methyl-imidazol-1-yl)-pyrimidin-4-yl]-piperazin-1-yl)pyrimidin-2-yl)-ethanol;1R-(4-{3R,5S-dimethyl-4-[2-(2-methyl-imidazol-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;1R-(4-{4-[2-(2,4-dimethyl-imidazol-1-yl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;1R-(4-{4-[2-(4-isopropyl-piperazin-1-yl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;1R-(4-{3R,5S-dimethyl-4-[4-methyl-6-(4-methyl-piperazin-1-yl)-[1,3,5]triazin-2-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;1R-{4-[4-(4-methoxy-6-methyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[4-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[4-(4-ethoxy-6-methyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[4-(4-isopropoxy-6-methyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[3R,5S-dimethyl-4-(4-phenyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[4-(4-hydroxymethyl-6-methoxy-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[4-(4-isopropoxy-6-methoxy-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[4-(4-isopropyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[4-(4-ethyl-6-methoxy-[1,3,5]triazin-2-yl)3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[4-(4,6-dimethyl-pyrimidin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[4-(4-hydroxymethyl-6-methyl-pyrimidin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-,ethanol;1R-{4-[2R,6S-dimethyl-4-(4-[1,2,4]triazol-1-yl-pyrimidin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[4-(2,6-dimethyl-pyrimidin-4-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;1R-{4-[4-(2-hydroxymethyl-6-methyl-pyrimidin-4-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-(4-{4-[2-(1S-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;1S-(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1{4-[4-(2-acetyl-pyrimidin-4-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanone;1RS-(4-{4-[2-(1RS-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl)pyrimidin-2-yl}-ethanol;(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanone;1R-{4-[2R,6S-dimethyl-4-(2-morpholin-4-yl-pyrimidin-4-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-(4-{2R,6S-dimethyl-4-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;1R{4-[2R,6S-dimethyl-4-(2-[1,2,4]triazol-1-yl-pyrimidin-4-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6R-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;1R-(4-{4-[2-(4-ethyl-piperazin-1-yl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;1R-(4-{2R,6S-dimethyl-4-[2-(4-methyl-imidazol-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;1R-(4-{4-[2-(2,4-dimethyl-imidazol-1-yl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;1R{4-[2R,6S-dimethyl-4-(4-morpholin-4-yl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R{4-[4-(4-methoxy-4-methyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}ethanol;1R-{4-[4-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-yl}-ethanol;1R-{4-[2R,6S-dimethyl-4-(4-phenyl-[1,3,5]-triazin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[4-(4-hydroxymethyl-6-methyl-pyrmidin-2-yl]3S-methyl-piperazin-yl]-pyrmidin-2-ylethanol; 1.R-[4-(2-hydroxymethyl-pyrimidin-4yl)-3S-methyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[4-(2-hydroxymethyl-6methyl-pyrimidin-4-yl)-3S-methyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-[4-(3S-methyl-4-oxazolo[5,4-b]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethanol;1R-[4-(3S-methyl-4-oxazolo[4,5-b]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethanol;1R-[4-(3S-methyl-4-quinoxalin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethanol;(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;1R-{4-[4-(4,6-dimethyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R{4-[3R,5S-dimethyl-4-(4-methyl-6-phenyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]pyrimidin-2-yl}-ethanol;1R-{4-[4-(4-cyclopropyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[4-(4-cyclopropyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[4-(4,6-dimethyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[4-(4-hydroxymethyl-6-phenyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[4-(4-methoxy-6-methoxymethyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[2R,6S-dimethyl-4-(4-methyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl-ethanol;1-{4-[4-(2-acetyl-pyrimidin-4-yl)-2-R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanone;1-(444-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanone;1R-{4-[4-(4-methoxymethyl-6-phenyl-[1,3,5]-triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;and 1S-(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol.

A compound of the formula 1 ^(A)

wherein:

-   R¹ is C—(OR⁸⁰)R⁴R⁵, where R⁸⁰ is independently (C₁-C₄)alkyl, benzyl,    (C₁-C₆)alkylcarbonyl or phenylcarbonyl, where said benzyl and said    phenyl are optionally substituted with up to three (C₁-C₄)alkyl,    (C₁-C₄)alkoxy, halo or nitro;-   R⁴ and R⁵ are each independently hydrogen, methyl, ethyl or    hydroxy-(C₁-C₃)alkyl;-   R² is hydrogen, (C₁-C₄)alkyl or (C₁-C₄)alkoxy;-   R³ is a radical of the formula-    wherein said radical of formula R^(3a) is substituted by R⁶, R⁷ and    R⁸; said radical of formula R^(3b) is substituted by R¹⁸, R¹⁹ and    R²⁰;-   G, G¹ and G² are taken separately and are each hydrogen and R⁶ is    hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxycarbonyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, hydroxy-(C₁-C₄)alkyl or phenyl    optionally independently substituted with up to three hydroxy, halo,    hydroxy-(C₁C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl or    (C₁-C₄)alkoxy, wherein said (C₁-C₄)alkyl in the definition of R⁶ and    said (C₁-C₄)alkoxy in the definition of R⁶ are, optionally and    independently substituted with up to five fluoro; R⁷ and R⁸ are each    independently hydrogen or (C₁-C₄)alkyl; or-   G and G¹ are taken together and are (C₁-C₃)alkylene and R⁶, R⁷, R⁸    and G² are hydrogen; or-   G¹ and G² are taken together and are (C₁-C₃)alkylene and R⁶, R⁷, R⁸    and G are hydrogen;-   q is 0 or 1;-   X is a covalent bond, —(C═NR¹⁰)—, oxycarbonyl, vinylenylcarbonyl,    oxy(C₁-C₄)alkylenylcarbonyl, (C₁-C₄)alkylenylcarbonyl,    (C₃-C₄)alkenylcarbonyl, thio(C₁-C₄)alkylenylcarbonyl,    vinylenylsulfonyl, sulfinyl-(C₁-C₄)alkylenylcarbonyl,    sulfonyl-(C₁-C₄)alkylenylcarbonyl or    carbonyl(C₀-C₄)alkylenylcarbonyl; wherein said    oxy(C₁-C₄)alkylenylcarbonyl, (C₁-C₄)alkylenylcarbonyl,    (C₃-C₄)alkenylcarbonyl and thio(C₁-C₄)alkylenylcarbonyl in the    definition of X are each optionally and independently substituted    with up to two (C₁-C₄)alkyl, benzyl or Ar; said vinylenylsulfonyl    and said vinylenylcarbonyl in the definition of X are optionally    substituted independently on one or two vinylenyl carbons with    (C₁-C₄)alkyl, benzyl or Ar; and said    carbonyl(C₀-C₄)alkylenylcarbonyl in the definition of X is    optionally substituted independently with up to three (C₁-C₄)alkyl,    benzyl or Ar;-   R¹⁰ is hydrogen or (C₁-C₄)alkyl;-   R⁹ is (C₃-C₇)cycloalkyl, Ar¹—(C₀-C₃)alkylenyl or (C₁-C₆)alkyl    optionally substituted with up to five fluoro; provided that when    q=0 and X is a covalent bond, oxycarbonyl or    (C₁-C₄)alkylenylcarbonyl, then R⁹ is not (C₁-C₆)alkyl;-   Ar and Ar¹ are independently a fully saturated, partially saturated    or fully unsaturated five- to eight-membered ring optionally having    up to four heteroatoms selected independently from oxygen, sulfur    and nitrogen, or a bicyclic ring consisting of two fused    independently partially saturated, fully saturated or fully    unsaturated five- to seven-membered rings, taken independently,    optionally having up to four heteroatoms selected independently from    nitrogen, sulfur and oxygen, or a tricyclic ring consisting of three    fused independently partially saturated, fully saturated or fully    unsaturated five to seven membered rings, taken independently,    optionally having up to four heteroatoms selected independently from    nitrogen, sulfur and oxygen, said partially saturated, fully    saturated ring or fully unsaturated monocyclic ring, bicyclic ring    or tricyclic ring optionally having one or two oxo groups    substituted on carbon or one or two oxo groups substituted on    sulfur;-   Ar and Ar¹ are optionally independently substituted on carbon or    nitrogen, on one ring if the moiety is monocyclic, on one or both    rings if the moiety is bicyclic, or on one, two or three rings if    the moiety is tricyclic, with up to a total of four substituents    independently selected from R¹¹, R¹², R¹³ and R¹⁴; wherein R¹¹, R¹²,    R¹³ and R¹⁴ are each taken separately and are each independently    halo, formyl, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylenyloxycarbonyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, C(OH)R¹⁵R¹⁶, naphthyl, phenyl,    imidazolyl, pyridyl, triazolyl, morpholinyl, (C₀-C₄)alkylsulfamoyl,    N-(C₀-C₄)alkylcarbamoyl, N,N-di-(C₁-C₄)alkylcarbamoyl,    N-phenylcarbamoyl, N-(C₁-C₄)alkyl-N-phenylcarbamoyl, N,N-diphenyl    carbamoyl, (C₁-C₄)alkylcarbonylamido,    (C₃-C₇)cycloalkylcarbonylamido, phenylcarbonylamido, piperidinyl,    pyrrolidinyl, piperazinyl, cyano, benzimidazolyl, amino, anilino,    pyrimidyl, oxazolyl, isoxazolyl, tetrazolyl, thienyl, thiazolyl,    benzothiazolyl, pyrrolyl, pyrazolyl, tetrahydroquinolyl,    tetrahydroisoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy,    pyridylsulfanyl, furanyl,    8-(C₁-C₄)alkyl-3,8-diaza[3.2.1]bicyclooctyl,    3,5-dioxo-1,2,4-triazinyl, phenoxy, thiophenoxy,    (C₁-C₄)alkylsulfanyl, (C₁-C₄)alkylsulfonyl, (C₃-C₇)cycloalkyl,    (C₁-C₄)alkyl optionally substituted with up to five fluoro or    (C₁-C₄)alkoxy optionally substituted with up to five fluoro; said    naphthyl, phenyl, pyridyl, piperidinyl, benzimidazolyl, pyrimidyl,    thienyl, benzothiazolyl, pyrrolyl, tetrahydroquinolyl,    tetrahydroisoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy,    pyridylsulfanyl, furanyl, thiophenoxy, anilino and phenoxy in the    definition of R¹¹, R¹², R¹³ and R¹⁴ are optionally substituted with    up to three substituents independently selected from hydroxy, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro and (C₁-C₄)alkoxy    optionally substituted with up to five fluoro; said imidazolyl,    oxazolyl, isoxazolyl, thiazolyl and pyrazolyl in the definition of    R¹¹, R¹², R¹³ and R¹⁴ are optionally substituted with up to two    substituents independently selected from hydroxy, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro and (C₁-C₄)alkoxy    optionally substituted with up to five fluoro; said morpholinyl in    the definition of R¹¹, R¹², R¹³ and R¹⁴ is optionally substituted    with up to two substituents independently selected from    (C₁-C₄)alkyl; said pyrrolidinyl in the definition of R¹¹, R¹², R¹³    and R¹⁴ is optionally substituted with up to two substituents    independently selected from hydroxy, hydroxy-(C₁-C₃)alkyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally substituted with    up to five fluoro and (C₁-C₄)alkoxy optionally substituted with up    to five fluoro; said piperazinyl in the definition of R¹¹, R¹², R¹³    and R¹⁴ is optionally substituted with up to three substituents    independently selected from (C₁-C₄)alkoxy(C₁-C₄)alkyl,    hydroxy-(C₁-C₃)alkyl, phenyl, pyridyl, (C₀-C₄)alkylsulfamoyl,    (C₁-C₄)alkyl optionally substituted with up to five fluoro and    (C₁-C₄)alkoxy optionally substituted with up to five fluoro; said    triazolyl in the definition of R¹¹, R¹², R¹³ and R¹⁴ is optionally    substituted with hydroxy, halo, hydroxy-(C₁-C₄)alkyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally substituted with    up to five fluoro and (C₁-C₄)alkoxy optionally substituted with, up    to five fluoro; said tetrazolyl in the definition of R¹¹, R¹², R¹³    and R¹⁴ is optionally substituted with hydroxy-(C₂-C₃)alkyl or    (C₁-C₄)alkyl optionally substituted with up to five fluoro; and said    phenyl and pyridyl which are optionally substituted on piperazine in    the definition of R¹¹, R¹², R¹³ and R¹⁴ are optionally substituted    with up to three hydroxy, halo, hydroxy-(C₁-C₄)alkyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally substituted with    up to five fluoro and (C₁-C₄)alkoxy optionally substituted with up    to five fluoro; or-   R¹¹ and R¹² are taken together on adjacent carbon atoms and are    —CH₂OC(CH₃)₂OCH₂— or —O—(CH₂)_(p)—O—, and R¹³ and R¹⁴ are taken    separately and are each independently hydrogen or (C₁-C₄)alkyl;-   p is 1, 2 or 3;-   R¹⁵ and R¹⁶ are taken separately and are each independently    hydrogen, (C₁-C₄)alkyl optionally substituted with up to five    fluoro; or R¹⁵ and R¹⁶ are taken separately and R¹⁵ is hydrogen and    R¹⁶ is (C₃-C₆)cycloalkyl, hydroxy-(C₁-C₃)alkyl, phenyl, pyridyl,    pyrimidyl, thienyl, furanyl, thiazolyl, oxazolyl, imidazolyl,    benzothiazolyl or benzoxazolyl; or R¹⁵ and R¹⁶ are taken together    and are (C₃-C₆)alkylene;-   G³, G⁴ and G⁵ are taken separately and are each hydrogen; r is 0;    R¹⁸ is hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxycarbonyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, hydroxy-(C₁-C₄)alkyl or phenyl    optionally independently substituted with up to three hydroxy, halo,    hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl or    (C₁-C₄)alkoxy, wherein said (C₁-C₄)alkyl in the definition of R⁶ and    said (C₁-C₄)alkoxy in the definition of R⁶ are optionally and    independently substituted with up to five fluoro; and R¹⁹ and R²⁰    are each independently (C₁-C₄)alkyl; or-   G³, G⁴ and G⁵ are taken separately and are each hydrogen; r is 1;    R¹⁸ is hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxycarbonyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, hydroxy-(C₁-C₄)alkyl or phenyl    optionally independently substituted with up to three hydroxy, halo,    hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl or    (C₁-C₄)alkoxy, wherein said (C₁-C₄)alkyl in the definition of R⁶ and    said (C₁-C₄)alkoxy in the definition of R⁶ are optionally and    independently substituted with up to five fluoro; and R¹⁹ and R²⁰    are each independently hydrogen or (C₁-C₄)alkyl; or-   G³ and G⁴ are taken together and are (C₁-C₃)alkylene; r is 0 or 1;    and R¹⁸, R¹⁹, R²⁰, and G⁵ are hydrogen; or-   G⁴ and G⁵ are taken together and are (C₁-C₃)alkylene; r is 0 or 1;    and R¹⁸, R¹⁹, R²⁰ and G³ are hydrogen;-   R¹⁷ is SO₂NR²¹R²², CONR²¹R²², (C₁-C₆)alkoxycarbonyl,    (C₁-C₆)alkylcarbonyl, Ar²-carbonyl, (C₁-C₆)alkylsulfonyl,    (C₁-C₆)alkylsulfinyl, Ar²-sulfonyl, Ar²-sulfinyl and (C₁-C₆)alkyl;-   R²¹ and R²² are taken separately and are each independently selected    from hydrogen, (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl and    Ar²—(C₀-C₄)alkylenyl; or R²¹ and R²² are taken together with the    nitrogen atom to which they are attached to form azetidinyl,    pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl,    azabicyclo[3.2.2]nonanyl, azabicyclo[2.2.1]heptyl,    6,7-dihydro-5H-dibenzo[c,e]azepinyl, 1,2,3,4-tetrahydro-isoquinolyl    or 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl; said azetidinyl in the    definition of R²¹ and R² is optionally substituted independently    with one substituent selected from hydroxy, amino,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro and (C₁-C₄)alkoxy    optionally substituted with up to five fluoro; said pyrrolidinyl,    piperidinyl, azepinyl in the definition of R²¹ and R²² are    optionally substituted independently with up to two substituents    independently selected from hydroxy, amino, hydroxy-(C₁-C₄)alkyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally substituted with    up to five fluoro and (C₁-C₄)alkoxy optionally substituted with up    to five fluoro; said morpholinyl in the definition of R²¹ and R²² is    optionally substituted with up to two substituents independently    selected from hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl,    (C₁-C₄)alkyl optionally substituted with up to five fluoro and    (C₁-C₄)alkoxy optionally substituted with up to five fluoro; said    piperazinyl in the definition of R²¹ and R²² is optionally    substituted independently with up to three substituents    independently selected from phenyl, pyridyl, pyrimidyl,    (C₁-C₄)alkoxy carbonyl and (C₁-C₄)alkyl optionally substituted With    up to five fluoro; said 1,2,3,4-tetrahydro-isoquinolyl and said    5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl in the definition of R²¹    and R²² are optionally substituted independently with up to three    substituents independently selected from hydroxy, amino, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro and (C₁-C₄)alkoxy    optionally substituted with up to five fluoro; and said    6,7-dihydro-5H-dibenzo[c,e]azepinyl in the definition of R²¹ and R²²    is optionally substituted with up to four substituents independently    selected from hydroxy, amino, halo, hydroxy-(C₁-C₄)alkyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally substituted with    up to five fluoro and (C₁-C₄)alkoxy optionally substituted with up    to five fluoro; said pyrimidyl, pyridyl and phenyl, which are    optionally substituted on said piperazine in the definition of R²¹    and R⁴ is optionally substituted with up to three substituents    selected from hydroxy, amino, hydroxy-(C₁-C₄)alkyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally substituted with    up to five fluoro and (C₁-C₄)alkoxy optionally substituted with up    to five fluoro;-   Ar² is independently defined as set forth for Ar and Ar¹ above;-   said Ar² is optionally independently substituted as set forth for Ar    and Ar¹ above;-   R²³ is CONR²⁵R²⁶ or SO₂R²⁵R²⁶, wherein R²⁵ is hydrogen (C₁-C₄)alkyl    or Ar³—(C₀-C₄)alkylenyl and R²⁶ is Ar³—(C₀-C₄)alkylenyl; provided    that when Ar³ is phenyl, naphthyl or biphenyl, then R²³ cannot be    CONR²⁵R²⁶ where R²⁵ is hydrogen or Ar³ and R²⁶ is Ar³;-   R²⁴ is hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxycarbonyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, hydroxy-(C₁-C₄)alkyl or phenyl    optionally independently substituted with up to three hydroxy, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl or    (C₁-C₄)alkoxy, wherein said (C₁-C₄)alkyl in the definition of R⁶ and    said (C₁-C₄)alkoxy in the definition of R⁶ are optionally and    independently substituted with up to five fluoro; Ar³ is    independently defined as set forth for Ar and Ar¹ above;-   said Ar³ is optionally independently substituted as set forth for Ar    and Ar¹ above;-   R²⁷ is hydrogen or (C₁-C₄)alkyl;-   R²⁸ and R²⁹ are each independently hydrogen, hydroxy, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro, (C₁-C₄)alkoxy    optionally substituted with up to five fluoro, phenyl, pyridyl,    pyrimidyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy,    thiophenoxy, SO₂NR³⁰R³¹, CONR³⁰R³¹ or NR³⁰R³¹; said thienyl,    pyrimidyl, furanyl, thiazolyl and oxazolyl in the definition of R²    and R²⁹ are optionally substituted by up to two hydroxy, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro or (C₁-C₄)alkoxy    optionally substituted with up to five fluoro; said phenyl, pyridyl,    phenoxy and thiophenoxy in the definition of R²⁸ and R²⁹ are    optionally substituted by up to three hydroxy, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro or (C₁-C₄)alkoxy    optionally substituted with up to five fluoro;-   R³⁰ and R³¹ are each independently hydrogen, (C₁-C₄)alkyl,    (C₃-C₇)cycloalkyl or phenyl, said phenyl is optionally substituted    with up to three hydroxy, halo, hydroxy(C₁-C₄)alkyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally substituted with    up to five fluoro or (C₁-C₄)alkoxy optionally substituted with up to    five fluoro; or-   R³⁰ and R³¹ are taken together with the nitrogen to which they are    attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl    or morpholinyl; said pyrrolidinyl and piperidinyl in the definition    of R³⁰ and R³¹ are optionally substituted with up to two hydroxy,    amino, hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl,    (C₁-C₄)alkyl optionally substituted with up to five fluoro or    (C₁-C₄)alkoxy optionally substituted with up to five fluoro; said    indolinyl and piperazinyl in the definition of R³⁰ and R³¹ are    optionally substituted with up to three hydroxy, amino,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl,    (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl optionally substituted with up    to five fluoro or (C₁-C₄)alkoxy optionally substituted with up to    five fluoro; said morpholinyl in the definition of R³⁰ and R³¹ is    optionally substituted with up to two substituents independently    selected from hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl,    (C₁-C₄)alkyl optionally substituted with up to five fluoro and    (C₁-C₄)alkoxy optionally substituted with up to five fluoro;-   A is N optionally substituted with hydrogen or (C₁-C₄)alkyl and B is    carbonyl; or-   A is carbonyl and B is N optionally substituted with hydrogen or    (C₁-C₄)alkyl;-   R³² is hydrogen or (C₁-C₄)alkyl;-   R³³ is phenyl, pyridyl, pyrimidyl, thiazolyl, oxazolyl, benzyl,    quinolyl, isoquinolyl, phthalizinyl, quinoxanlyl, benzothiazoyl,    benzoxazolyl, benzofuranyl or benzothienyl; said phenyl, pyridyl,    pyrimidyl, thiazolyl, oxazolyl, benzyl, quinolyl, isoquinolyl,    phthalizinyl, quinoxanlyl, benzothiazoyl, benzoxazolyl, benzofuranyl    and benzothienyl in the definition of R³³ are optionally substituted    with up to three phenyl, phenoxy, NR³⁴R³⁵, halo, hydroxy,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro or, (C₁-C₄)alkoxy    optionally substituted with up to five fluoro;-   R³⁴ and R³⁵ are each independently hydrogen, (C₁-C₄ alkyl), phenyl    or phenylsulfonyl; said phenyl and phenylsulfonyl in the definition    of R³⁴ and R³⁵ are optionally substituted with up to three halo,    hydroxy, (C₁-C₄)alkyl optionally substituted with up to five fluoro    or (C₁-C₄)alkoxy optionally substituted with up to five fluoro;-   D is CO, CHOH or CH₂;-   E is O, NH or S;-   R³⁶ and R³⁷ are taken separately and are each independently    hydrogen, halo, cyano, hydroxy, amino, (C₁-C₆)alkylamino,    di-(C₁-C₆)alkylamino, pyrrolidino, piperidino, morpholino,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, hydroxy-(C₁-C₄)alkyl, Ar⁴, (C₁-C₄)alkyl    optionally substituted with up to five fluoro or (Q₁-C₄)alkoxy    optionally substituted with up to five fluoro;-   R³⁸, R³⁹ and R⁴⁰ are each independently hydrogen or (C₁-C₄)-alkyl;-   Ar⁴ is phenyl, furanyl, thienyl, pyridyl, pyrimidyl, pyrazinyl or    pyridazinyl; said Ar⁴ being optionally substituted with up to three    hydroxy, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, halo, hydroxy-(C₁-C₄)alkyl,    (C₁-C₄)alkyl optionally substituted with up to five fluoro or    (C₁-C₄)alkoxy optionally substituted with up to five fluoro; or-   R³⁶ and R³⁷ are taken together on adjacent carbon atoms and are    —O—(CH₂)_(t)—O—;-   t is 1, 2 or 3;-   Y is (C₂-C₆)alkylene;-   R⁴⁴, R⁴⁵ and R⁴⁶ are each independently hydrogen or (C₁-C₄)alkyl;-   m and n are each independently 1, 2 or 3, provided that the sum of m    and n is 2, 3 or 4;-   k is 0, 1, 2, 3 or 4;-   Y¹ is a covalent bond, carbonyl, sulfonyl or oxycarbonyl;-   R⁴³ is (C₃-C₇)cycloalkyl, Ar⁵—(C₀-C₄)alkylenyl, NR⁴⁷R⁴⁸ or    (C₁-C₆)alkyl optionally substituted with one to five fluoro;    provided that when Y¹ is a covalent bond or oxycarbonyl, then R⁴ is    not NR⁴⁷R⁴⁸;-   R⁴⁷ and R⁴⁸ are taken separately and are each independently selected    from hydrogen, Ar⁵, (C₁-C₆)alkyl and Ar⁵—(C₀-C₄)alkylenyl; or-   R⁴⁷ and R⁴⁸ are taken together with the nitrogen atom to which they    are attached to form azetidinyl, pyrrolidinyl, piperidinyl,    piperazinyl, morpholinyl, azepinyl, azabicyclo[3.2.2]nonanyl,    azabicyclo[2.2.1]heptyl, 1,2,3,4-tetrahydroisoquinolyl,    6,7-dihydro-5H-dibenzo[c,e]azepinyl or    5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl; said azetidinyl in the    definition of R⁴⁷ and Re are optionally substituted with one    hydroxy, amino, hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl,    (C₁-C₄)alkyl optionally substituted with up to five fluoro or    (C₁-C₄)alkoxy optionally substituted with up to five fluoro; said    pyrrolidinyl, piperidinyl and azepinyl in the definition of R⁴⁷ and    R⁴⁸ are optionally substituted with up to two hydroxy, amino,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro or (C₁-C₄)alkoxy    optionally substituted with up to five fluoro; said morpholinyl in    the definition of R⁴⁷ and R⁴⁸ is optionally substituted with up to    two substituents independently selected from hydroxy-(C₁-C₄)alkyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally substituted with    up to five fluoro and (C₁-C₄)alkoxy optionally substituted with up    to five fluoro; said piperazinyl, 1,2,3,4-tetrahydroisoquinolyl and    5,6,7,8-tetrahydro[4,3-d]pyrimidyl in the definition of R⁴⁷ and R⁴⁸    are optionally substituted with up to three hydroxy, amino, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro or (C₁-C₄)alkoxy    optionally substituted with up to five fluoro; and said    6,7-dihydro-5H-dibenzo[c,e]azepinyl in the definition of R⁴⁷ and R⁴⁸    are optionally substituted with up to four hydroxy, amino, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro or (C₁-C₄)alkoxy    optionally substituted with up to five fluoro;-   Ar⁵ is independently defined as set forth for Ar and Ar¹ above;-   Ar is optionally independently substituted as set forth for Ar and    Ar¹ above;-   R⁴² and R^(42a) are independently hydrogen, (C₃-C₇)cycloalkyl,    Ar⁶—(C₀-C₃)alkylenyl, Ar⁶—(C₂-C₄)alkenyl, Ar⁶-carbonyl or    (C₁-C₆)alkyl optionally substituted with up to five fluoro;-   Ar⁶ is independently defined as set forth for Ar and Ar¹ above;-   Ar⁶ is optionally independently substituted as set forth for Ar and    Ar¹ above; and-   R⁴¹ and R^(41a) are each independently hydrogen or (C₁-C₄)alkyl.

A compound of formula 1^(A) selected from1R-(4-{4-[2-(1R-butyryloxy-ethyl)pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethylbutyrate;1R-(44-[2-(1S-butyryloxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl)pyrimidin-2-yl)ethylbutyrate;1S-(4-{4-[2-(1R-butyryloxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethylbutyrate;(E)-1R-{4-[4-(2-methyl-32-phenyl-acryloyl)-piperazin-1-yl]-pyrimidin-2-yl}-ethylacetate;(R)-1-[4-(4-quinoxalin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethylacetate;1R-(4{4-[2-(1RS-hydroxy-ethyl)-pyrimidin-4-yl]-72R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethylbutyrate; 1RS-(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]3R,5S-dimethyl-pyrimidin-2-yl)-ethylbutyrate;1R-[4(3S-methyl-4-oxazolo[5,4-b]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethylbutyrate;1R-{4-[3R,5S-dimethyl-4-(4-methyl-6-phenyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethylbutyrate; 1R-4-{4-[4-(4cyclopropyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin2-yl}-ethyl butyrate;1R-{4-[4-(4-cyclopropyl-[1,3,5]-triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}thylbutyrate;1R-{4-[4-(4,6-dimethyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethylbutyrate;1R-{4-[4-(4-hydroxymethyl-6-phenyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethylbutyrate;1R-{4-[4-(4-methoxy-6-methoxymethyl-[1,3,5]triazin-2-yl)-R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}thylbutyrate; and1R-{4-[2R,6S-dimethyl-4-(4-methyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethylbutyrate.

This invention is also directed to a mutual prodrug of the formulaI^(B),

wherein:

-   R¹ is C—(OR⁸¹)R⁴R⁵, where R⁸¹ is independently an acyl radical of a    carboxylic acid aldose reductase inhibitor;-   R⁴ and R⁵ are each independently hydrogen, methyl, ethyl or    hydroxy-(C₁-C₃)alkyl;-   R² is hydrogen, (C₁-C₄)alkyl or (C₁-C₄)alkoxy;-   R³ is a radical of the formula-    wherein said radical of formula R^(3a) is substituted by R⁶, R⁷ and    R⁸;-   said radical of formula R^(3b) is substituted by R¹⁸, R¹⁹ and R²⁰;-   G, G¹ and G² are taken separately and are each hydrogen and R⁶ is    hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxycarbonyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, hydroxy-(C₁-C₄)alkyl or phenyl    optionally independently substituted with up to three hydroxy, halo,    hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl or    (C₁-C₄)alkoxy, wherein said (C₁-C₄)alkyl in the definition of R⁶ and    said (C₁-C₄)alkoxy in the definition of R⁶ are optionally and    independently substituted with up to five fluoro; R⁷ and R⁸ are each    independently hydrogen or (C₁-C₄)alkyl; or-   G and G¹ are taken together and are (C₁-C₃)alkylene and R⁶, R⁷, R⁸    and G² are hydrogen; or-   G¹ and G² are taken together and are (C₁-C₃)alkylene and R⁶, R⁷, R⁸    and G are hydrogen;-   q is 0 or 1;-   X is a covalent bond, —(C═NR¹⁰)—, oxycarbonyl, vinylenylcarbonyl,    oxy(C₁-C₄)alkylenylcarbonyl, (C₁-C₄)alkylenylcarbonyl,    (C₃-C₄)alkenylcarbonyl, thio(C₁-C₄)alkylenylcarbonyl,    vinylenylsulfonyl, sulfinyl-(C₁-C₄)alkylenylcarbonyl,    sulfonyl-(C₁-C₄)alkylenylcarbonyl or    carbonyl(C₀-C₄)alkylenylcarbonyl; wherein said    oxy(C₁-C₄)alkylenylcarbonyl, (C₁-C₄)alkylenylcarbonyl,    (C₃-C₄)alkenylcarbonyl and thio(C₁-C₄)alkylenylcarbonyl in the    definition of X are each optionally and independently substituted    with up to two (C₁-C₄)alkyl, benzyl or Ar; said vinylenylsulfonyl    and said vinylenylcarbonyl in the definition of X are optionally    substituted independently on one or two vinylenyl carbons with    (C₁-C₄)alkyl, benzyl or Ar; and said    carbonyl(C₀-C₄)alkylenylcarbonyl in the definition of X is    optionally substituted independently with up to three (C₁-C₄)alkyl,    benzyl or Ar;-   R¹⁰ is hydrogen or (C₁-C₄)alkyl;-   R⁹ is (C₃-C₇)cycloalkyl, Ar¹—(C₀-C₃)alkylenyl or (C₁-C₆)alkyl    optionally substituted with up to five fluoro; provided that when    q=0 and X is a covalent bond, oxycarbonyl or    (C₁-C₄)alkylenylcarbonyl, then R⁹ is not (C₁-C₆)alkyl;-   Ar and Ar¹ are independently a fully saturated, partially saturated    or fully unsaturated five- to eight-membered ring optionally having    up to four heteroatoms selected independently from oxygen, sulfur    and nitrogen, or a bicyclic ring consisting of two fused    independently partially saturated, fully saturated or fully    unsaturated five to seven-membered rings, taken independently,    optionally having up to four heteroatoms selected independently from    nitrogen, sulfur and oxygen, or a tricyclic ring consisting of three    fused independently partially saturated, fully saturated or fully    unsaturated five to seven membered rings, taken independently,    optionally having up to four heteroatoms selected independently from    nitrogen, sulfur and oxygen, said partially saturated, fully    saturated ring or fully unsaturated monocyclic ring, bicyclic ring    or tricyclic ring optionally having one or two oxo groups    substituted on carbon or one or two oxo-0 groups substituted on    sulfur;-   Ar and Ar¹ are optionally independently substituted on carbon or    nitrogen, on one ring if the moiety is monocyclic, on one or both    rings if the moiety is bicyclic, or on one, two or three rings if    the moiety is tricyclic, with up to a total of four substituents    independently selected from R¹¹, R¹², R¹³ and R¹⁴; wherein R¹¹, R¹²,    R¹³ and R¹⁴ are each taken separately and are each independently    halo, formyl, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylenyloxycarbonyl,    (C₄-C₄)alkoxy-(C₁-C₄)alkyl, C(OH)R¹⁵R¹⁶, naphthyl, phenyl,    imidazolyl, pyridyl, triazolyl, morpholinyl, (C₀-C₄)alkylsulfamoyl,    N-(C₀-C₄)alkylcarbamoyl, N,N-di-(C₁-C₄)alkylcarbamoyl,    N-phenylcarbamoyl, N-(C₁-C₄)alkyl-N-phenylcarbamoyl, N,N-diphenyl    carbamoyl, (C₁-C₄)alkylcarbonylamido,    (C₃-C₇)cycloalkylcarbonylamido, phenylcarbonylamido, piperidinyl,    pyrrolidinyl, piperazinyl, cyano, benzimidazolyl, amino, anilino,    pyrimidyl, oxazolyl, isoxazolyl, tetrazolyl, thienyl, thiazolyl,    benzothiazolyl, pyrrolyl, pyrazolyl, tetrahydroquinolyl,    tetrahydroisoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy,    pyridylsulfanyl, furanyl,    8-(C₁-C₄)alkyl-3,8-diaza[3.2.1]bicyclooctyl,    3,5-dioxo-1,2,4-triazinyl, phenoxy, thiophenoxy,    (C₁-C₄)alkylsulfanyl, (C₁-C₄)alkylsulfonyl, (C₃-C₇)cycloalkyl,    (C₁-C₄)alkyl optionally substituted with up to five fluoro or    (C₁-C₄)alkoxy optionally substituted with up to five fluoro; said    naphthyl, phenyl, pyridyl, piperidinyl, benzimidazolyl, pyrimidyl,    thienyl, benzothiazolyl, pyrrolyl, tetrahydroquinolyl,    tetrahydroisoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy,    pyridylsulfanyl, furanyl, thiophenoxy, anilino and phenoxy in the    definition of R¹¹, R¹², R¹³ and R¹⁴ are optionally substituted with    up to three substituents independently selected from hydroxy, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro and (C₁-C₄)alkoxy    optionally substituted with up to five fluoro; said imidazolyl,    oxazolyl, isoxazolyl, thiazolyl and pyrazolyl in the definition of    R¹¹, R¹², R¹³ and R¹⁴ are optionally substituted with up to two    substituents independently selected from hydroxy, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro and (C₁-C₄)alkoxy    optionally substituted with up to five fluoro; said morpholinyl in    the definition of R¹¹, R¹², R¹³ and R¹⁴ is optionally substituted    with up to two substituents independently selected from    (C₁-C₄)alkyl; said pyrrolidinyl in the definition of R¹¹, R¹², R¹³    and R¹⁴ is optionally substituted with up to two substituents    independently selected from hydroxy, hydroxy-(C₁-C₃)alkyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally substituted with    up to five fluoro and (C₁-C₄)alkoxy optionally substituted with up    to five fluoro; said piperazinyl in the definition of R¹¹, R¹², R¹³    and R¹⁴ is optionally substituted with up to three substituents    independently selected from (C₁-C₄)alkoxy(C₁-C₄)alkyl,    hydroxy-(C₁-C₃)alkyl, phenyl, pyridyl, (C₀-C₄)alkylsulfamoyl,    (C₁-C₄)alkyl optionally substituted with up to five fluoro and    (C₁-C₄)alkoxy optionally substituted with up to five fluoro; said    triazolyl in the definition of R¹¹, R¹², R¹³ and R¹⁴ is optionally    substituted with hydroxy, halo, hydroxy-(C₁-C₄)alkyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally substituted with    up to five fluoro and (C₁-C₄)alkoxy optionally substituted with up    to five fluoro; said tetrazolyl in the definition of R¹¹, R¹², R¹³    and R¹⁴ is optionally substituted with hydroxy-(C₂-C₃)alkyl or    (C₁-C₄)alkyl optionally substituted with up to five fluoro; and said    phenyl and pyridyl which are optionally substituted on piperazine in    the definition of R¹¹, R¹², R¹³ and R¹⁴ are optionally substituted    with up to three hydroxy, halo, hydroxy-(C₁-C₄)alkyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally substituted with    up to five fluoro and (C₁-C₄)alkoxy optionally substituted with up    to five fluoro; or-   R¹¹ and R¹² are taken together on adjacent carbon atoms and are    —CH₂OC(CH₃)₂OCH₂— or —O—(CH₂)_(p)—O—, and R¹³ and R¹⁴ are taken    separately and are each independently hydrogen or (C₁-C₄)alkyl;-   p is 1, 2 or 3;-   R¹⁵ and R¹5 are taken separately and are each independently    hydrogen, (C₁-C₄)alkyl optionally substituted with up to five    fluoro; or R¹⁵ and R¹⁶ are taken separately and R¹⁵ is hydrogen and    R¹⁶ is (C₃-C₆)cycloalkyl, hydroxy-(C₁-C₃)alkyl, phenyl, pyridyl,    pyrimidyl, thienyl, furanyl, thiazolyl, oxazolyl, imidazolyl,    benzothiazolyl or benzoxazolyl; or R¹⁵ and R¹⁶ are taken together    and are (C₃-C₆)alkylene;-   G³, G⁴ and G⁵ are taken separately and are each hydrogen; r is 0;    R¹⁸ is hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxycarbonyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, hydroxy-(C₁-C₄)alkyl or phenyl    optionally independently substituted with up to three hydroxy, halo,    hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl or    (C₁-C₄)alkoxy, wherein said (C₁-C₄)alkyl in the definition of R⁶ and    said (C₁-C₄)alkoxy in the definition of R⁶ are optionally and    independently substituted with up to five fluoro; and R¹⁹ and R²⁰    are each independently, C₁-C₄)alkyl; or-   G³, G⁴ and G⁵ are taken separately and are each hydrogen; r is 1;    R¹⁸ is hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxycarbonyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, hydroxy-(C₁-C₄)alkyl or phenyl    optionally independently substituted with up to three hydroxy, halo,    hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl or    (C₁-C₄)alkoxy, wherein said (C₁-C₄)alkyl in the definition of R⁶ and    said (C₁-C₄)alkoxy in the definition of R⁶ are optionally and    independently substituted with up to five fluoro; and R¹⁹ and R² are    each independently hydrogen or (C₁-C₄)alkyl; or-   G³ and G⁴ are taken together and are (C₁-C₃)alkylene; r is 0 or 1;    and R¹⁸, R¹⁹, R²⁰ and G⁵ are hydrogen; or-   G⁴ and G⁵ are taken together and are (C₁-C₃)alkylene; r is 0 or 1;    and R¹⁸, R¹⁹, R²⁰ and G³ are hydrogen;-   R¹⁷ is SO₂NR²¹R², CONR²¹R²², (C₁-C₆)alkoxycarbonyl,    (C₁-C₆)alkylcarbonyl, Ar²-carbonyl, (C₁-C₆)alkylsulfonyl,    (C₁-C₆)alkylsulfinyl, A_-sulfonyl, Ar²-sulfinyl and (C₁-C₆)alkyl;-   R²¹ and R²² are taken separately and are each independently selected    from hydrogen, (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl and    Ar²—(C₀-C₄)alkylenyl; or-   R²¹ and R²² are taken together with the nitrogen atom to which they    are attached to form azetidinyl, pyrrolidinyl, piperidinyl,    piperazinyl, morpholinyl, azepinyl, azabicyclo[3.2.2]nonanyl,    azabicyclo[2.2.1]heptyl, 6,7-dihydro-5H-dibenzo[c,e]azepinyl,    1,2,3,4-tetrahydro-isoquinolyl or    5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl; said azetidinyl in the    definition of R²¹ and R²² is optionally substituted independently    with one substituent selected from hydroxy, amino,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro and (C₁-C₄)alkoxy    optionally substituted with up to five fluoro; said pyrrolidinyl,    piperidinyl, azepinyl in the definition of R²¹ and R²² are    optionally substituted independently with up to two substituents    independently selected from hydroxy, amino, hydroxy-(C₁-C₄)alkyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally substituted with    up to five fluoro and (C₁-C₄)alkoxy optionally substituted with up    to five fluoro; said morpholinyl in the definition of R²¹ and R²² is    optionally substituted with up to two substituents independently    selected from hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl,    (C₁-C₄)alkyl optionally substituted with up to five fluoro and    (C₁-C₄)alkoxy optionally substituted with up to five fluoro; said    piperazinyl in the definition of R²¹ and R² is optionally    substituted independently with up to three substituents    independently selected from phenyl, pyridyl, pyrimidyl,    (C₁-C₄)alkoxycarbonyl and (C₁-C₄)alkyl optionally substituted with    up to five fluoro; said 1,2,3,4-tetrahydro-isoquinolyl and said    5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl in the definition of R²¹    and R²² are optionally substituted independently with up to three    substituents independently selected from hydroxy, amino, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro and (C₁-C₄)alkoxy    optionally substituted with up to five fluoro; and said    6,7-dihydro-5H-dibenzo[c,e]azepinyl in the definition of R²¹ and R²    is optionally substituted with up to four substituents independently    selected from hydroxy, amino, halo, hydroxy-(C₁-C₄)alkyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally substituted with    up to five fluoro and (C₁-C₄)alkoxy optionally substituted with up    to five fluoro; said pyrimidyl, pyridyl and phenyl which are    optionally substituted on said piperazine in the definition of R²¹    and R²² is optionally substituted with up to three substituents    selected from hydroxy, amino, hydroxy-(C₁-C₄)alkyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally substituted with    up to five fluoro and (C₁-C₄)alkoxy optionally substituted with up    to five fluoro;-   Ar² is independently defined as set forth for Ar and Ar¹ above;-   said Ar² is optionally independently substituted as set forth for Ar    and Ar¹ above;-   R²³ is CONR²⁵R²⁶ or SO₂R²⁵R²⁶, wherein R²⁵ is hydrogen (C₁-C₄)alkyl    or Ar³—(C₀-C₄)alkylenyl and R²⁶ is Ar³—(C₀-C₄)alkylenyl; provided    that when Ar³ is phenyl, naphthyl or biphenyl, then R²³ cannot be    CONR²⁵R²⁶ where R²⁵ is hydrogen or Ar and R²⁶ is Ar³;-   R²⁴ is hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxycarbonyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, hydroxy-(C₁-C₄)alkyl or phenyl    optionally independently substituted with up to three hydroxy, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl or    (C₁-C₄)alkoxy, wherein said (C₁-C₄)alkyl in the definition of R⁶ and    said (C₁-C₄)alkoxy in the definition of R⁶ are optionally and    independently substituted with up to five fluoro;-   Ar³ is independently defined as set forth for Ar and Ar¹ above;-   said Ar³ is optionally independently substituted as set forth for Ar    and Ar¹ above;-   R²⁷ is hydrogen or (C₁-C₄)alkyl;-   R²⁸ and R²⁹ are each independently hydrogen, hydroxy, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro, (C₁-C₄)alkoxy    optionally substituted with up to five fluoro, phenyl, pyridyl,    pyrimidyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy,    thiophenoxy, SO₂NR³⁰R³¹, CONR³⁰R³¹ or NR³⁰R³¹; said thienyl,    pyrimidyl, furanyl, thiazolyl and oxazolyl in the definition of R²⁸    and R²⁹ are optionally substituted by up to two hydroxy, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro or (C₁-C₄)alkoxy    optionally substituted with up to five fluoro; said phenyl, pyridyl,    phenoxy and thiophenoxy in the definition of R²⁸ and R² are    optionally substituted by up to three hydroxy, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro or (C₁-C₄)alkoxy    optionally substituted with up to five fluoro;-   R³⁰ and R³¹ are each independently hydrogen, (C₁-C₄)alkyl,    (C₃-C₇)cycloalkyl or phenyl, said phenyl is optionally substituted    with up to three hydroxy, halo, hydroxy(C₁-C₄)alkyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally substituted with    up to five fluoro or (C₁-C₄)alkoxy optionally substituted with up to    five fluoro; or-   R³⁰ and R³¹ are taken together with the nitrogen to which they are    attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl    or morpholinyl; said pyrrolidinyl and piperidinyl in the definition    of R³⁰ and R³¹ are optionally substituted with up to two hydroxy,    amino, hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl,    (C₁-C₄)alkyl optionally substituted with up to five fluoro or    (C₁-C₄)alkoxy optionally substituted with up to five fluoro; said    indolinyl and piperazinyl in the definition of R³⁰ and R³¹ are    optionally substituted with up to three hydroxy, amino,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl,    (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl optionally substituted with up    to five fluoro or (C₁-C₄)alkoxy optionally substituted with up to    five fluoro; said morpholinyl in the definition of R³⁰ and R³¹ is    optionally substituted with up to two substituents independently    selected from hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl,    (C₁-C₄)alkyl optionally substituted with up to five fluoro and    (C₁-C₄)alkoxy optionally substituted with up to five fluoro;-   A is N optionally substituted with hydrogen or (C₁-C₄)alkyl and B is    carbonyl; or-   A is carbonyl and B is N optionally substituted with hydrogen or    (C₁-C₄)alkyl;-   R³² is hydrogen or (C₁-C₄)alkyl;-   R³³ is phenyl, pyridyl, pyrimidyl, thiazolyl, oxazolyl, benzyl,    quinolyl, isoquinolyl, phthalizinyl, quinoxanlyl, benzothiazoyl,    benzoxazolyl, benzofuranyl or benzothienyl; said phenyl, pyridyl,    pyrimidyl, thiazolyl, oxazolyl, benzyl, quinolyl, isoquinolyl,    phthalizinyl, quinoxanlyl, benzothiazoyl, benzoxazolyl, benzofuranyl    and benzothienyl in the definition of R³³ are optionally substituted    with up to three phenyl, phenoxy, NR³⁴R³⁵, halo, hydroxy,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro or (C₁-C₄)alkoxy    optionally substituted with up to five fluoro;-   R³⁴ and R³⁵ are each independently hydrogen, (C₁-C₄ alkyl), phenyl    or phenylsulfonyl; said phenyl and phenylsulfonyl in the definition    of R³¹ and R³⁵ are optionally substituted with up to three halo,    hydroxy, (C₁-C₄)alkyl optionally substituted with up to five fluoro    or (C₁-C₄)alkoxy optionally substituted with up to five fluoro;-   D is CO, CHOH or CH₂;-   E is O, NH or S;-   R³⁶ and R³⁷ are taken separately and are each independently    hydrogen, halo, cyano, hydroxy, amino, (C₁-C₆)alkylamino,    di-(C₁-C₆)alkylamino, pyrrolidino, piperidino, morpholino,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, hydroxy-(C₁-C₄)alkyl, Ar⁴, (C₁-C₄)alkyl    optionally substituted with up to five fluoro or (C₁-C₄)alkoxy    optionally substituted with up to five fluoro;-   R³⁸, R³⁹ and R⁴⁰ are each independently hydrogen or (C₁-C₄)-alkyl;-   Ar⁴ is phenyl, furanyl, thienyl, pyridyl, pyrimidyl, pyrazinyl or    pyridazinyl; said Ar⁴ being optionally substituted with up to three    hydroxy, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, halo, hydroxy-(C₁-C₄)alkyl,    (C₁-C₄)alkyl optionally substituted with up to five fluoro or    (C₁-C₄)alkoxy optionally substituted with up to five fluoro; or-   R³⁶ and R³⁷ are taken together on adjacent carbon atoms and are    —O—(CH₂)_(t)—O—;-   t is 1, 2 or 3;-   Y is (C₂-C₆)alkylene;-   R⁴⁴, R⁴⁵ and R⁴⁶ are each independently hydrogen or (C₁-C₄)alkyl;-   m and n are each independently 1, 2 or 3, provided that the sum of m    and n is 2, 3 or 4;-   k is 0, 1, 2, 3 or 4;-   Y¹ is a covalent bond, carbonyl, sulfonyl or oxycarbonyl;-   R⁴³ is (C₃-C₇)cycloalkyl, Ar⁵—(C₀-C₄)alkylenyl, NR⁴⁷R⁴⁸ or    (C₁-C₆)alkyl optionally substituted with one to five fluoro;    provided that when Y¹ is a covalent bond or oxycarbonyl, then R⁴³ is    not NR⁴⁷R⁴⁸;-   R⁴⁷ and R⁴⁸ are taken separately and are each independently selected    from hydrogen, Ar⁵, (C₁-C₆)alkyl and Ar⁵—(C₀-C₄)alkylenyl; or-   R⁴⁷ and R⁴⁸ are taken together with the nitrogen atom to which they    are attached to form azetidinyl, pyrrolidinyl, piperidinyl,    piperazinyl, morpholinyl, azepinyl, azabicyclo[3.2.2]nonanyl,    azabicyclo[2.2.1]heptyl, 1,2,3,4-tetrahydroisoquinolyl,    6,7-dihydro-5H-dibenzo[c,e]azepinyl or    5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl; said azetidinyl in the    definition of R⁴⁷ and R⁴⁸ are optionally substituted with one    hydroxy, amino, hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl,    (C₁-C₄)alkyl optionally substituted with up to five fluoro or    (C₁-C₄)alkoxy optionally substituted with up to five fluoro; said    pyrrolidinyl, piperidinyl and azepinyl in the definition of R⁴⁷ and    R⁴⁸ are optionally substituted with up to two hydroxy, amino,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro or (C₁-C₄)alkoxy    optionally substituted with up to five fluoro; said morpholinyl in    the definition of R⁴⁷ and R⁴⁸ is optionally substituted with up to    two substituents independently selected from hydroxy-(C₁-C₄)alkyl,    (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally substituted with    up to five fluoro and (C₁-C₄)alkoxy optionally substituted with up    to five fluoro; said piperazinyl, 1,2,3,4-tetrahydroisoquinolyl and    5,6,7,8-tetrahydro[4,3-d]pyrimidyl in the definition of R⁴⁷ and R⁴⁸    are optionally substituted with up to three hydroxy, amino, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro or (C₁-C₄)alkoxy    optionally substituted with up to five fluoro; and said    6,7-dihydro-5H-dibenzo[c,e]azepinyl in the definition of R⁴⁷ and R⁴⁸    are optionally substituted with up to four hydroxy, amino, halo,    hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl    optionally substituted with up to five fluoro or (C₁-C₄)alkoxy    optionally substituted with up to five fluoro;-   Ar⁵ is independently defined as set forth for Ar and Ar¹ above;-   Ar⁵ is optionally independently substituted as set forth for Ar and    Ar¹ above;-   R⁴² and R^(42a) are independently hydrogen, (C₃-C₇)cycloalkyl,    Ar⁶—(C₀-C₃)alkylenyl, Ar⁵—(C₂-C₄)alkenyl, Ar⁶-carbonyl or    (C₁-C₆)alkyl optionally substituted with up to five fluoro;-   Ar⁶ is independently defined as set forth for Ar and Ar¹ above;-   Ar⁶ is optionally independently substituted as set forth for Ar and    Ar¹ above; and-   R⁴¹ and R^(41a) are each independently hydrogen or (C₁-C₄)alkyl.

A preferred group of compounds within the compound of formula I^(B) arethose compounds wherein R⁸¹ is the acyl radical of ponalrestat,tolrestat, zenarastat, zopolrestat, epalrestat, ZD5522 or sorbinil.

Especially preferred mutual prodrugs of this invention are selected from(E)-[4-oxo-3-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-3,4-dihydro-phthalazin-1-yl]-aceticacid 1R-[4-(4-quinoxalin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethylester and(E)-[4-Oxo-3-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-3,4-dihydro-phthalazin-1-yl]-aceticacid1R-{4-[4-(3-thiophen-2-yl-acryloyl)-piperazin-1-yl]-pyrimidin-2-yl}thylester.

This invention is also directed to intermediate compounds of the formulaZ

This invention is still further directed to intermediate compounds,designated Group M, of the formula ZZ,

wherein R¹⁰⁰ is (C₁-C₈)alkyl, benzyl or phenyl wherein said benzyl andphenyl are optionally substituted with up to three halo or (C₁-C₄)alkyl.

A preferred group of compounds within Group M, designated Group AB, arethose compounds wherein R¹⁰⁰ is (C₁-C₄)alkyl.

More preferred compounds within the Group AB are those compounds whereinR¹⁰⁰ is n-butyl or ethyl.

This invention is still further directed to a compound of the formulaZZZ,

wherein:

-   R¹⁰⁰ is (C₁-C₈)alkyl, benzyl or phenyl wherein said benzyl and    phenyl are optionally substituted with, up to three halo or    (C₁-C₄)alkyl; and-   R¹⁰¹ is hydrogen or a suitable amine protecting group.

A preferred group of compounds of formula ZZZ, designated Group AC, arethose compounds wherein R¹⁰⁰ is (C₁-C₄)alkyl and R¹⁰¹ is benzyl ortert-butyloxycarbonyl.

A preferred group of compounds within the Group AC are those compoundswherein R¹⁰⁰ is n-butyl or ethyl and R¹⁰¹ is benzyl.

Another preferred group of compounds within the Group AC are thosecompounds wherein R¹¹° is n-butyl or ethyl and R¹⁰¹ istert-butyloxycarbonyl.

This invention is also directed to a process for preparing a compound ofthe formula Z,

comprising:

-   -   a) reacting R-(+)-2-hydroxy-propionamide with triethyloxonium        tetrafluoroborate in a reaction inert solvent for 10 minutes to        24 hours at 0° C. to ambient temperature to form the        corresponding imidate;    -   b) reacting said corresponding imidate with anhydrous ammonia in        a reaction inert solvent for 2 hours to 24 hours at 0° C. to        ambient temperature to form R-(+)-2-hydroxy-propionamidine        hydrochloride; and    -   c) reacting said R-(+)-2-hydroxy-propionamidine hydrochloride        with ethyl 3-hydroxy-acrylate sodium salt and a suitable base in        a reaction inert solvent to form said compound of formula Z.

This invention is also directed to a pharmaceutical composition,designated Composition M, comprising a compound of claim 1, a prodrugthereof or a pharmaceutically acceptable salt of said prodrug or saidcompound, and a glycogen phosphorylase inhibitor (GPI), a prodrug ofsaid GPI or a pharmaceutically acceptable salt of said GPI or saidprodrug.

This invention is also directed to a kit comprising:

-   -   a. a compound of claim 1, a prodrug thereof or a        pharmaceutically acceptable salt of said prodrug or said        compound in a first unit dosage form;    -   b. a glycogen phosphorylase inhibitor (GPI), a prodrug thereof        or a pharmaceutically acceptable salt of said prodrug or said        GPI in a second unit dosage form; and    -   c. a container.

This invention is also directed to a method of treating or preventingdiabetic complications in a mammal comprising administering to saidmammal a pharmaceutical composition of Composition M.

This invention is also directed to a method of treating hyperglycemia ina mammal comprising administering to said mammal a pharmaceuticalcomposition of Composition M.

This invention is also directed to a method of treating ischemia in amammal suffering from ischemia comprising administering to said mammal apharmaceutical composition of Composition M.

This invention is also directed to a method of treating diabetes in a,mammal comprising administering to said mammal a pharmaceuticalcomposition of Composition M.

This invention is also directed to a method of treating diabeticcomplications in a mammal comprising administering to said mammal acompound of formula I, a prodrug thereof or a pharmaceuticallyacceptable salt of said compound or said prodrug and a glycogenphosphorylase inhibitor (GPI), a prodrug of said GPI or apharmaceutically acceptable salt of said GPI or said prodrug.

This invention is also directed to a method of treating hyperglycemia ina mammal comprising administering to said mammal a compound of formulaI, a prodrug thereof or a pharmaceutically acceptable salt of saidcompound or said prodrug and a glycogen phosphorylase inhibitor (GPI), aprodrug of said GPI or a pharmaceutically acceptable salt of said GPI orsaid prodrug.

This invention is also directed to a method of treating ischemia in amammal comprising administering to said mammal a compound of formula I,a prodrug thereof or a pharmaceutically acceptable salt of said compoundor said prodrug and a glycogen phosphorylase inhibitor (GPI), a prodrugof said GPI or a pharmaceutically acceptable sail of said GPI or saidprodrug.

This invention is also directed to a method of treating diabetes in amammal comprising administering to said mammal a compound of formula I,a prodrug thereof or a pharmaceutically acceptable salt of said compoundor said prodrug and a glycogen phosphorylase inhibitor (GPI), a prodrugof said GPI or a pharmaceutically acceptable salt of said GPI or saidprodrug.

The subject invention also includes isotopically-labeled compounds,which are identical to those recited in Formula I, but for the fact thatone or more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, sulfur, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C,¹⁵N, ¹⁶O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively. Compounds ofthe present invention, prodrugs thereof, and pharmaceutically acceptablesalts of said compounds or of said prodrugs which contain theaforementioned isotopes and/or other isotopes of other atoms are withinthe scope of this invention. Certain isotopically-labeled compounds ofthe present invention, for example those into which racioactive isotopessuch as ³H and ¹⁴C are incorporated, are useful in drug and/or substratetissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e.,¹⁴C, isotopes are particularly preferred for their ease of preparationand detectability. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically labeled compounds of Formula I of thisinvention and prodrugs thereof can generally be prepared by carrying outthe procedures disclosed in the Schemes and/or in the Examples andPreparations below, by substituting a readily available isotopicallylabeled reagent for a non-isotopically labeled reagent.

The term “reduction” is intended to include partial prevention orprevention which, although greater than that which would result fromtaking no compound or from taking a placebo, is less than 100% inaddition to substantially total prevention.

The term “damage resulting from ischemia” as employed herein refers toconditions directly associated with reduced blood flow to tissue, forexample due to a clot or obstruction of blood vessels which supply bloodto the subject tissue and which result, inter alia, in lowered oxygentransport to such tissue, impaired tissue performance, tissuedysfunction and/or necrosis. Alternatively, where blood flow or organperfusion may be quantitatively adequate, the oxygen carrying capacityof the blood or organ perfusion medium may be reduced, e.g., in hypoxicenvironment, such that oxygen supply to the tissue is lowered, andimpaired tissue performance, tissue dysfunction, and/or tissue necrosisensues.

The term “treating”, “treat” or “treatment” as used herein includespreventative (e.g., prophylactic) and palliative treatment.

By “pharmaceutically acceptable” it is meant the carrier, diluent,excipients, and/or salt must be compatible with the other ingredients ofthe formulation, and not deleterious to the recipient thereof.

The expression “prodrug” refers to compounds that are drug precursorswhich following administration, release the drug in vivo via somechemical or physiological, process (e.g., a prodrug on being brought tothe physiological pH or through enzyme action is converted to thedesired drug form).

This invention is further directed to compounds which are mutualprodrugs of aldose reductase inhibitors and sorbitol dehydrogenaseinhibitors. By mutual prodrug is meant a compound which contains twoactive components, in this case, an aldose reductase inhibitor and asorbitol dehydrogenase inhibitor, which, following administration, iscleaved, releasing each individual active component. Such mutualprodrugs of an aldose reductase inhibitor and a sorbitol dehydrogenaseinhibitor are formed under standard esterification conditions well knownto those skilled in the art.

By alkylene is meant saturated hydrocarbon (straight chain or branched)wherein a hydrogen atom is removed from each of the terminal carbons.Exemplary of such groups (assuming the designated length encompasses theparticular example) are methylene, ethylene, propylene, butylene,pentylene, hexylene, heptylene.

By halo is meant chloro, bromo, iodo, or fluoro.

By alkyl is meant straight chain saturated hydrocarbon or branchedsaturated hydrocarbon. Exemplary of such alkyl groups (assuming thedesignated length encompasses the particular example) are methyl, ethyl,propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl,neopentyl, tertiary pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,hexyl, isohexyl, heptyl and octyl.

By alkoxy is meant straight chain saturated alkyl or branched saturatedalkyl bonded through an oxygen. Exemplary of such alkoxy groups(assuming the designated length encompasses the particular example) aremethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiarybutoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy,isohexoxy, heptoxy and octoxy.

It is to be understood that if a carbocyclic or heterocyclic moiety maybe bonded or otherwise attached to a designated substrate throughdiffering ring atoms without denoting a specific point of attachment,then all possible points are intended, whether through a carbon atom or,for example, a trivalent nitrogen atom. For example, the term “pyridyl”means 2-, 3-, or 4-pyridyl, the term “thienyl” means 2-, or 3-thienyl,and so forth.

The expression “pharmaceutically-acceptable salt” refers to nontoxicanionic salts containing anions such as (but not limited to) chloride,bromide, iodide, sulfate, bisulfate, phosphate, acetate, maleate,fumarate, oxalate, lactate, tartrate, citrate, gluconate,methanesulfonate and 4-toluene-sulfonate. Where more than one basicmoiety exists the expression includes multiple salts (e.g., di-salt).The expression also refers to nontoxic cationic salts such as but notlimited to) sodium, potassium, calcium, magnesium, ammonium orprotonated benzathine (N,N′-dibenzylethylenediamine), choline,ethanolamine, diethanolamine, ethylenediamine, meglamine(N-methyl-glucamine), benethamine (N-benzylphenethylamine), piperazineor tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol).

As used herein, the expressions “reaction inert solvent” and “inertsolvent” refers to a solvent or mixture of solvents which does notinteract with starting materials, reagents, intermediates or products ina manner which adversely affects the yield of the desired product.

The chemist of ordinary skill will recognize that certain compounds offormula I of this invention will contain one or more atoms which may bein a particular stereochemical or geometric configuration, giving riseto stereoisomers and configurational isomers. All such isomers andmixtures thereof are included in this invention. Compounds of formula Imay be chiral. In such cases, the isomer wherein R¹ has the Rconfiguration is preferred. Hydrates of the compounds of formula I ofthis invention are also included.

The chemist of ordinary skill in the art will also recognize thatcertain compounds of formula I of this invention can exist in tautomericform, i.e., that an equilibrium exists between two isomers which are inrapid equilibrium with each other. A common example of tautomerism isketo-enol tautomerism, i.e.,

Examples of compounds which can exist as tautomers includehydroxypyridines, hydroxypyrmidines and hydroxyquinolines. Otherexamples will be recognized by those skilled in the art. All suchtautomers and mixtures thereof are included in this invention.

DMF means N,N-dimethylformamide. DMSO means dimethyl sulfoxide. THFmeans tetrahydrofuran.

Whenever the structure of a cyclic radical is shown with a bond drawnfrom outside the ring to inside the ring, it will be understood by thoseof ordinary skill in the art to mean that the bond may be attached toany atom on the ring with an available site for bonding. If the cyclicradical is a bicyclic or tricyclic radical, then the bond may beattached to any atom on any of the rings with an available site forbonding. For example,

represents any or all of the following radicals:

Other features and advantages will be apparent from the specificationand claims which describe the invention.

DETAILED DESCRIPTION OF THE INVENTION

In general the compounds of formula I of this invention can be made byprocesses which include processes known in the chemical arts,particularly in light of the description contained herein. Certainprocesses for the manufacture of the compounds of formula I of thisinvention are provided as further features of the invention and areillustrated by the following reaction schemes. Other processes aredescribed in the experimental section.

Compounds of formula I-3 (i.e., formula I) are prepared as set forth inScheme 1, particularly as described below.

Compounds of formula I-3 are prepared by the displacement reaction of apyrimidine of the formula I-1 where R¹ and R² are defined herein. Lv isa leaving group preferably selected from fluoro, chloro, bromo, iodo,thiomethyl, methylsulfone, or OSO₂J wherein J is (C₁-C₆)-lower alkyl,trifluoromethyl, pentafluoroethyl, phenyl optionally substituted with upto three (C₁-C₄)alkyl, nitro or halo. The leaving group Lv is displacedby an amine of the formula I-2 where R³ is defined above. The reactionis conducted in the presence of a non-aqueous base, preferably anorganic amine or an inorganic base. Preferred organic amines includetriethylamine, pyridine, dimethylaminopyridine andN,N′-diisopropylethylamine (Hunig's base). Preferred inorganic basesinclude alkaline metal carbonates and bicarbonates such as sodium orpotassium carbonate and sodium or potassium bicarbonate. An especiallypreferred inorganic base is potassium carbonate. An especially preferredorganic amine is triethylamine. Alternatively, an excess of the reactingamine 1-2 can be used as the base for this reaction. The reaction can beconducted in the absence of solvent or in a reaction inert solvent.Where used herein, “reaction inert solvent” refers to a solvent whichdoes not interact with starting materials, reagents, intermediates orproducts in a manner which adversely affects the yield of the desiredproduct. Preferred reaction inert solvents include aqueous media,pyridine, (C₁-C₄)alcohol, (C₂-C₆)glycol, halocarbon, aliphaticlaromatichydrocarbon, ethereal solvent, polar aprotic solvent, ketonic solvent,or combinations thereof. The reaction time ranges from 15 minutes to 3days and the reaction temperature ranges from 0° C. to 180° C.Conveniently, the reaction may be conducted at the reflux temperature ofthe solvent being used. The reaction is preferably conducted at ambientpressure. The term ambient pressure, where used herein, refers to thepressure of the room in which the reaction is being conducted. The termambient temperature, where used herein, refers to the temperature of theroom in which the reaction is being conducted.

When R¹ contains a hydroxy group, the hydroxyl group may or may not beprotected. When the hydroxyl group is protected, the protecting groupmay be any suitable hydroxyl protecting group. The conditions used toremove such optional hydroxyl protecting groups contained in R¹ incompounds of formula I-3 are as follows. When the protecting group is anester, removal of such ester protecting groups is conducted under basicconditions using inorganic hydroxides or It carbonates, preferablylithium hydroxide, sodium hydroxide, potassium hydroxide or potassiumcarbonate. The reaction is carried out in a reaction inert solvent,preferably an alcoholic solvent. Especially preferred is methanol ormethanol in combination with co-solvents such as water, tetrahydrofuran,or dioxane. The reaction time ranges from 15 minutes to 24 hours and thereaction temperature ranges from 0° C. to 100° C. or to the refluxtemperature of the solvent(s) of use. Alternatively, ester cleavage maybe accomplished under acidic conditions. It is preferred to utilizeaqueous hydrochloric acid, generally 2 N to concentrated, with orwithout a co-solvent. When a co-solvent is used, dioxane or methanol arepreferred. The reaction time ranges from 4 hours to 3 days and thereaction temperature ranges from 0° C. to 60° C.

When the protecting group is an alkyl ether, removal of such alkyl etherprotecting groups is conducted using well known dealkylative conditions.For example, the alkyl ether may be cleaved by reaction with borontribromide or diethylboron bromide in a reaction inert solvent,preferably a halocarbon solvent. It will be recognized by those skilledin the art that a buffer such as triethylamine may facilitate thereaction. The reaction times range from 15 minutes to 24 hours and thereaction temperature ranges from 0° C. to 60° C. In addition, a benzylether protecting group can be removed via standard or transferhydrogenolysis using a palladium catalyst such as palladium on carbon.The hydrgenolysis reaction is conducted under a hydrogen atmosphere atambient pressure to 50 psi in a reaction inert solvent, preferablymethanol. The hydrogen source, may be hydrogen gas, ammonium, formate ortrialkylammonium formate or cyclohexene. The reaction temperature rangesfrom room temperature to the reflux temperature of the solvent employed.The reaction time ranges from 15 minutes to 24 hours.

When a silyl ether protecting group is employed, removal of such silylether protecting groups is conducted under acidic conditions, preferablywith aqueous hydrochloric acid such as 1 N to 6 N hydrochloric acid. Thede-protection may be carried out in the presence of a co-solvent such asmethanol or tetrahydrofuran. The reaction time ranges from 2 hours to 48hours and the reaction temperature ranges from 0° C. to 100° C.Alternatively, the silyl ether protecting group may be removed viafluoride-mediated deprotection. In this case, deprotection is conductedusing tetrabutylammonium fluoride or one of a variety of hydrofluoricacid sources in a reaction inert solvent. It is preferred to useethereal solvents such as diethyl ether, dioxane or tetrahydrofuran,with tetrahydrofuran being especially preferred. The reaction timeranges from 2 hours to 48 hours and the reaction temperatures range from0° C. to the reflux temperature of the solvent being used. Other methodsfor removal of the aforementioned protecting groups are well known tothose skilled in the art or can be found in Greene, T. W.; Wuts, P. G.M., Protective Groups in Organic Synthesis, 2^(nd) ed.; John Wiley andSons Inc.: New York, 1991. Other suitable hydroxyl protecting groups andmethods for their removal may be found also be found therein.

The method of Scheme I is preferred when R³ is R^(3k,l,m,n,o,p and q).Thus, compounds of formula I-2 are reacted with compounds of formulaI-1. Compounds of formula I-2 where R³ is R^(3k,l,m,n,o,p, or q) arecommercially available or can be prepared by methods well known to thoseskilled in the art.

Compounds of formula 2-7 are prepared as set forth in Scheme 2,particularly as described below.

Where R²⁷ is H, ethyl 1-benzyl-3-oxo-4-piperidine-carboxylatehydrochloride, the compound of formula 2-1, which is available fromAldrich, is condensed with compounds of formula 2-2 to give compounds offormula 2-3. The compounds of formula 2-1 where R²⁷ is not H can beprepared according to methods well known to those skilled in the art.The reaction is conducted in the presence of excess base includingnon-aqueous bases, organic amines and inorganic bases. Preferred organicamines include triethylamine and pyridine. Preferred non-aqueous basesinclude alkaline metal (C₁-C₄)alkoxides. Preferred inorganic basesinclude potassium carbonate. The reaction is conducted in a reactioninert solvent. Preferred such solvents include (C₁-C₄)alcohols, aromaticor aliphatic hydrocarbons, polar aprotic solvents, halocarbons, andethereal solvents. (C₁-C₄)Alcohols are especially preferred. Thereaction time ranges from 2 hours to 3 days. The reaction temperatureranges from ambient temperature to the reflux temperature of the solventbeing employed. The reaction is preferably run at ambient pressure butmay be conducted at pressures up to 250 psi.

Compounds of formula 24 are prepared from compounds of formula 2-3 byconverting a compound of formula 2-3 into an activated compound offormula 24 where Lv¹ is selected from fluoro, chloro, bromo, iodo,trifluoromethanesulfonate, (C₁-C₆)alkylsulfonate, or phenylsulfonate,wherein said phenyl is optionally substituted with up to three(C₁-C₄)alkyl, halo or nitro. This reaction is accomplished by reactingcompounds of formula 2-3 with a chlorinating agent such as phosphorusoxychloride and/or phosphorus pentachloride to provide compounds offormula 24 where Lv¹ is chloro. This reaction is conducted at ambientpressure in the absence of solvent or in a reaction inert solvent,preferably a halocarbon solvent at temperatures ranging from ambienttemperature to 180° C. Treatment of the chloro compound thus formed withthe requisite mineral acid provides a compound of formula 24 where Lv¹is bromo or iodo. A sulfonate of formula 24 is prepared by reaction of acompound of formula 2-3 with a sulfonic acid chloride or anhydride inthe presence of an organic amine base, preferably triethylamine orpyridine. In certain cases recognized by those skilled in the art, itmay be necessary to add a catalyst to the reaction. In those cases, apreferred catalyst is 4-dimethylaminopyridine. This reaction isconducted at ambient pressure in a reaction inert solvent, preferablypyridine, a halocarbon such as chloroform, dichloromethane or carbontetrachloride, an aromatic or aliphatic hydrocarbon, an etherealsolvent, or combinations thereof. The reaction temperature ranges from−20° C. to 100° C. and the reaction time ranges from 15 minutes to 1day.

Compounds of formula 2-5 wherein R² is defined above are prepared fromcompounds of formula 24 by a reduction reaction or by displacement ofLv¹ with a nucleophile. The reduction is conducted with a reducingagent, preferably ammonium formate or hydrogen gas, in a reaction inertsolvent. The reduction is conducted in the presence of a palladiumcatalyst at ambient pressure or under a hydrogen pressure of up to 50psi. Preferred solvents include (C₁-C₄)alcohols such as methanol andethanol, and ether solvents such as diethyl ether, dioxane andtetrahydrofuran. The nucleophilic displacement reaction may be conductedby adding the nucleophile directly or by pre-forming the nucleophileseparately or in situ from a nucleophile precursor. Preferrednucleophiles include organoaluminum, organoboron, organocopper,organotin, organozinc or Grignard reagent; R²⁹—H; or, where R²⁹ containsa hydroxyl or thiol group, the anion of R²⁹. The term “organo” in theterms organoaluminum, organoboron, organocopper, organotin andorganozinc refers to an organic radical selected from R²⁹. It will berecognized by those skilled in the art that transition-metal catalystsmay be required to effect reaction in certain displacement reactions.When required, such transition metal catalysts may include palladium(0),palladium(II), nickel(0), and nickel(II) complexes. Palladium(II)bis(diphenylphosphinobutane) dichloride is a preferred such catalyst.Additionally, an aqueous or non-aqueous base may be required in thedisplacement reaction. Preferred such bases include sodium carbonate,sodium hydride, triethylamine and sodium tert-butoxide. The reaction isconducted at ambient pressure in a reaction inert solvent such as ahalocarbon, an aromatic or aliphatic hydrocarbon, an ether or a polaraprotic solvent or a combination thereof. In certain cases, a(C₁-C₄)alcohol is used as a solvent or co-solvent. The reactiontemperature ranges from −20° C. to the reflux temperature of the solventemployed. The reaction time ranges from 1 hour to 3 days.

Compounds of formula 2-6 are prepared by removal of the benzylprotecting group from compounds of formula 2-3 or 2-5. Thistransformation is accomplished using the freebase, or preferably thepre-formed hydrochloride or similar salt, under standard or transferhydrogenolysis conditions. The catalysts which may be used in thehydrogenolysis reaction include, but are not limited to, palladium oncarbon, palladium hydroxide on carbon and platinum(IV) oxide. Thereaction is conducted in a reaction inert solvent, preferably methanolor ethanol and the reaction temperature ranges from room temperature tothe reflux temperature of the solvent being employed. The hydrogensource is hydrogen gas, ammonium formate, trialkylammonium formate, orcyclohexene. The reaction time ranges from 15 minutes to Generally thereaction is conducted at ambient pressure but pressures of up to 50 psiof hydrogen may be employed. Alternatively, if appropriate, the benzylprotecting group is removed in two steps via chloroformate-inducedacylative dealkylation. This involves reaction with a chloroformatederivative to form a carbamate followed by cleavage of the carbamate.While this reaction is preferably conducted with 1 chloroethylchloroformate and sodium iodide catalysis, it will be recognized bythose skilled in the art that catalysis may not be required in certaincases. The reaction is conducted at ambient temperature in a reactioninert solvent such as a halocarbon an aromatic or aliphatic hydrocarbon,a ketone, an ether or a polar aprotic solvent. The reaction temperatureranges from −78° C. to the reflux temperature of the solvent beingemployed and the reaction time ranges from 15 minutes to 1 day. Cleavageof the carbamate formed by reaction with 1-chloroethyl chloroformate isaccomplished upon exposure to methanol or ethanol at ambient pressure togive compounds of formula 2-6 as a hydrochloride salt. The reactionproceeds at temperatures from room temperature to the reflux temperatureof the solvent being employed and the reaction time ranges from 15minutes to 1 day. Deprotection conditions for other carbamates can befound in Greene, T. W.; Wuts, P. G. M. Protective Groups in OrganicSynthesis, 2^(nd) ed.; John Wiley and Sons Inc.: New York, 1991, pp315-348.

Compounds of formula 2-7 are prepared from the displacement reaction ofamine 2-6 as described in Scheme 1, where the amine 2-6 is equivalent toR³—NH.

Alternatively, compounds of formula 2-7 where R²⁹ is as defined aboveare prepared from compounds of formula 2-3 wherein R²⁹ is OH accordingto the sequence outlined in Scheme 2a below, wherein the conditions areas set forth as described for Scheme 2.

Compounds of formula 2-2 which are used in Schemes 2 and 2a above arecommercially available or are prepared according to methods well knownto those skilled in the art, such as those described in March, J.Advanced Organic Chemistry, 3^(rd) ed.; John Wiley and Sons.: New York,1985, p 359, 374.

Compounds of formula 3-5 are prepared as set forth in Scheme 3 above andmore particularly as described below.

Compounds of formula 3-3 are prepared by condensing a compound offormula 3-1 with a compound of formula 3-2. Where R³⁸ and R³⁹ are eachH, the compound of formula 3-1 is 1-benzyl-4-piperidone, which iscommercially available from Aldrich. Compounds of formula 3-2 are eithercommercially available or can be prepared according to methods wellknown to those skilled in the art, particularly according to methods setforth in March, J. Advanced Organic Chemistry, 3^(rd) ed.; John Wileyand Sons Inc.: New York, 1985, pp 499-500. The reaction is conducted atambient pressure in the presence of a secondary amine. Generally anexcess of the secondary amine, preferably pyrrolidine, piperidine,morpholine or diethylamine, is used. An especially preferred secondaryamine is pyrrolidine. The reaction is conducted in a reaction inertsolvent, preferably a (C₁-C₄)alcohol, an aromatic or aliphatichydrocarbon, a polar aprotic solvent, a halocarbon or an ether. Anespecially preferred solvent is ethanol. The reaction time ranges from 2hours to 3 days and the reaction temperature ranges from ambienttemperature to the reflux temperature of the solvent being employed.

Compounds of the formula 34 are prepared, by removal of the benzylprotecting group from compounds of formula 3-3. This transformation isconducted in a manner analogous to the procedure set forth for thepreparation of compounds of formula 2-6 above.

Compounds of formula 3-5 are prepared from the displacement reaction ofamine 34 as described in Scheme 1, where the amine 34 is equivalent toR³—NH.

Compounds of formulas 3a-1 and 3a-2 are prepared as shown in Scheme 3afrom compounds of formula 3-5. Thus, to prepare a compound of 3a-1, acompound of formula 3-5 is reduced with a common reducing agent, suchas, for example, sodium borohydride, lithium aluminum hydride ordiisobutylaluminum hydride. Other reducing agents capable of effectingthe reduction of a ketone to an alcohol are well known to those skilledin the art (e.g., Larock, R. D. Comprehensive Organic Transformations,VCH Publishers, Inc.: New York, 1989, pp 527-547). Likewise, compoundsof formula 3a-2 are prepared from compounds of formula 3-5 by reductionwith reducing agents capable of reducing a ketone completely to amethylene group. A preferred such reducing agent is aluminumtrichloride/borane-tert-butylamine complex. Other such reducing agentsare well known to those skilled in the art (e.g., J. Org. Chem. 1989,54, 4350; Larock, R. D. Comprehensive Organic Transformations, VCHPublishers, Inc.: New York, 1989, pp 35-37) it will be recognized bythose skilled in the art that the transformation of 13-5 to 3a-1 or 3a-2can be conducted at different points in Scheme 3, depending upon thedynamics of the particular system.

Alternatively, compounds of formula 3-5 wherein R³⁸ and R³⁹ are hydrogencan be prepared from 4-piperidone monohydrate monochloride in a manneranalogous to the procedure described in Scheme 1, where the amine 36 isequivalent to R³—NH to give compounds of formula 3-7. Compounds offormula 3-7, can be reacted with compounds of formula 3-2 in a manneranalogous to the procedure set forth for the synthesis of compounds offormula 3-3 to afford compounds of formula 3-5.

Compounds of formula 4-5 are prepared according to Scheme 4 and moreparticularly as described below.

Compounds of formula 4-3 are prepared by reacting a compound of formula4-2 with a compound of formula 4-1 or 4-1a. Compounds of formula 4-1 and4-1a are prepared according to methods well known to those skilled inthe art. Where R³² is hydrogen, 4-oxo-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-ethyl ester is condensed with a compound of formula4-2 to afford a compound of formula 4-3. Said compounds of formula 4-2are readily available from well known commercial vendors, known in theliterature, or are synthesized under standard conditions well, known tothose skilled in the art. Preferred conditions to prepare compounds offormula 4-3 from a compound of formula 4-1 where A is CO and B is NH orfrom a compound of formula 4-1a where A is NH and B is CO can be foundin March, J. Advanced Organic Chemistry, 3^(rd) ed.; John Wiley and SonsInc.: New York, 1985, p 1163. The reaction is conducted at ambientpressure in a reaction inert solvent. Preferred such solvents includeaqueous media, a (C₁-C₄)alcohol, glacial acetic acid, an aromatic oraliphatic hydrocarbon, a polar aprotic solvent, a halocarbon and ethersor combinations thereof. The reaction time ranges from 2 hours to 3 daysand the reaction temperature ranges from ambient temperature to thereflux temperature of the solvent being used. An optional second stepusing aqueous or non-aqueous base may be employed in certain cases whichwill be recognized by those skilled in the art. This second step isconducted at ambient pressure in a reaction inert solvent. Preferredsuch solvents include aqueous media, a (C₁-C₄)alcohol, glacial aceticacid, an aromatic or aliphatic hydrocarbon, a polar aprotic solvent, ahalocarbon and ethers or combinations thereof. The reaction time rangesfrom 2 hours to 3 days and the reaction temperature ranges from ambienttemperature to the reflux temperature of the solvent being used.

Compounds of formula 4-3 wherein B is CO and A is N-alkyl or wherein Bis N-alkyl and A is CO are prepared by alkylation of compounds offormula 4-3 where B is CO and A is NH or wherein B is NH and A is CO,respectively. The anion of those compounds of formula 4-3 is formed byreaction with an appropriate base. Preferred such bases include sodiumhydride and sodium hexamethyldisilazide, although other bases may beused where conditions warrant, as determined by the skilled person. Thereaction is conducted in a reaction inert solvent, preferably an ethersuch as tetrahydrofuran, diethyl ether, dioxane or diglyme or polaraprotic solvent such as dimethylformamide. The reaction proceeds atambient pressure and at temperatures ranging from −100° C. to ambienttemperature. The reaction times are from 10 minutes to 2 hours. Additionof (C₁-C₄)alkyl halides or (C₁-C₄)alkylsulfonates such as mesylate,tosylate or nosylate to the anion of 4-3 proceeds at ambient pressureand at temperatures ranging from −20° C. to 50° C. The reaction timesrange from 10 minutes to 1 day.

Compounds of formula 44 are prepared form compounds of formula 4-3wherein A is N-alkyl and B is Cd or A is CO and B is N-alkyl viaacid-catalyzed deproteciion of the Boc carbamate under standardconditions, for example, hydrochloric, acid or trifluoroacetic acid in areaction inert solvent or in the absence of solvent. Such conditions areknown to those skilled in the art. Exemplary conditions are disclosed inGreene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis,2^(nd) ed., John Wiley and Sons Inc.: New York, 1991, pp 327-330.

Compounds of formula 4-5 are prepared by the displacement reaction ofamine 44, as described in Scheme 1, where the amine 44 is equivalent toR³—H.

Compounds of formula 54 where X is a covalent bond and G, G¹, G², q, R¹,R², R⁶, R⁷ and R⁸ are as defined above are prepared according to Scheme5 above and particularly as described below.

Compounds of formula 5-3 are prepared by reaction of a compound offormula 5-1 with a compound of formula 5-2 where Prt is an optionalamine protecting group selected from benzyl and CO₂R⁹⁰, where R⁹⁰ isselected from (C₀-C₄)alkyl, (C₁-C₄)alkyl, trichloroethyl and benzylsubstituted by up to two (C₁-C₄)alkoxy. Compounds of formula 5-1 whereR⁹ is Ar¹ and Lv³ is halo, (C₁-C₄)alkylsulfide, (C₁-C₄)alkylsulfone,trifluoromethanesulfonate, (C₁-C₆)alkylsulfonate or phenylsulfonate,where said phenyl is optionally substituted with up to three halo, nitroor (C₁-C₄)alkyl are commercially available or are readily preparedaccording to methods well known to those skilled in the art. Forexample, to prepare compounds of formula 5-1 wherein Lv³ is chloro, acompound of formula Ar¹—OH, or the Ar¹—(═O) tautomer thereof, is reactedwith a chlorinating agent such as phosphorus oxychloride and/orphosphorus pentachloride. This chlorinating reaction is conducted atambient pressure in the absence of solvent or in a reaction inertsolvent, preferably a halocarbon solvent, at temperatures ranging fromambient temperature to 180° C. Treatment of the chloro compound with therequisite mineral acid provides compounds of formula 5-1 where Lv³ isbromo or iodo. Compounds of formula 5-1 wherein Lv³ istrifluoromethanesulfonate, (C₁-C₆)alkylsulfonate or phenylsulfonate areprepared from a compound of formula Ar¹—OH, or the Ar¹═O) tautomerthereof, by reaction with a sulfonic acid chloride or anhydride in thepresence of a base, preferably an organic amine such as triethylamine,N,N′-diisopropylethylamine, dimethylaminopyridine or pyridine. Incertain cases it will be recognized by those skilled in the art that acatalyst will be required to effect reaction. In those cases, apreferred catalyst is 4-dimethylaminopyridine. This reaction isconducted at ambient pressure in a reaction inert solvent such aspyridine, a halocarbon, an aromatic or aliphatic hydrocarbon, an ether,or a combination thereof. The reaction temperature ranges from −20° C.to 100° C. and the reaction time ranges from 15 minutes to 1 day.Compounds of formula 5-1 where Lv³ is thiomethyl are prepared byreacting a compound of formula Ar¹—SH, or the Ar¹—(═S) tautomer thereof,with methyl iodide or dimethylsulfate in the presence of an inorganicbase, preferably potassium carbonate. These reactions are conducted atambient pressure in a reaction inert solvent, preferably an ether or apolar aprotic solvent. An especially preferred polar aprotic solvent isdimethylformamide at a temperature ranging from 0° C. to 100° C.Compounds of formula 5-1 where Lv³ is methylsulfone are prepared from acompound of formula 5-1 where Lv³ is thiomethyl by oxidation thereofaccording to procedures well known to those skilled in the art,specifically as set forth in March, J. Advanced Organic Chemistry, 3tded.; John Wiley and Sons.: New York, 1985, pp 1089-1090.

A representative set of compounds of formula 5-1 which are commerciallyavailable or which can be prepared according to methods analogous to aliterature procedure include, 4-chloropyridine (Aldrich, P.O. Box 355,Milwaukee, Wis. 53201, USA), 3-chloro-6-methyl-pyridazine (Maybridge,c/o Ryan Scientific, 443 Long Point Road, Suite D, Mount Pleasant, S.C.29464, USA), 2-chloro-pyrazine (Aldrich), 2,6-dichloro-pyrazine(Aldrich), 3-chloro-2,5-dimethylpyrazine (Aldrich),2,4-dichloro-pyrimidine (Aldrich), 4,6-dichloro-pyrimidine, Aldrich),4-chloro-2-methyl-pyrimidine (Chem. Ber. 1904, 37, 3641),4-chloro-6-methyl-pyrmidine (Chem. Ber. 1899, 32, 2931),4-chloro-2,6-dimethyl-pyrimidine (J. Am. Chem. Soc. 1946, 68, 1299),4-chloro-2,6-bis(trifluoromethyl)-pyrimidine (J. Org. Chem. 1961, 26,4504), 4-chloro-2-methylsulfanyl-pyrimidine (Aldrich),4-chloro-2-methoxymethyl-pyrimidine (U.S. Pat. No. 5,215,990),1-chloro-isoquinoline (J. Am. Chem. Soc. 1946, 68, 1299),2-chloro-quinoline (Aldrich), 4-chloro-quinazoline (J. Am. Chem. Soc.1909, 31, 509), 2-chloro-quinoxaline (U.S. Pat. No. 2,537,870),2-chloro-3-methyl-quinoxaline (Aldrich), 2,6,7-trichloro-quinoxaline (J.Chem. Soc. Chem. Commun. 1956, 4731), 4-chloro-pteridine (J. Chem. Soc.Chem. Commun. 1954, 3832), 7-chloro-pteridine (J. Chem. Soc. Chem.Commun. 1954, 3832), and 6-chloro-9H-purine (Aldrich). Other compoundsof formula 5-1 can be prepared using methods well known to those skilledin the art or by using methods analogous to those described in theforegoing references.

Compounds of formula 5-3 are prepared by the displacement reaction of acompound of formula 5-1 with an amine of the formula 5-2. The reactionis conducted in the presence of a non-aqueous base, prefeably an organicamine such as pyridine, 4-dimethylaminopyridine, triethylamine orN,N′-diisopropylethylamine; an inorganic base such as potassium orsodium carbonate or bicarbonate; or an alkaline metal alkoxide such aspotassium t-butoxide. Alternatively, an excess of the reacting amine 5-2can be used in lieu of the added base. In cases where the leaving groupLv³ is unactivated, or in specific cases which will be recognized bythose skilled in the art, the use of a transition-metal catalyst such aspalladium(0), palladium (II), nickel(0) or nickel(II), along withphosphine-based ligands, such as 2,2′-bis(diphenylphosphino)1,1′-binaphthyl (BINAP), may be required to effect reaction. Morespecific details concerning this reaction are available in the followingreferences: J. Org. Chem. 1997, 62, 1264; J. Org. Chem. 1997, 62, 1568;SynLett 1997, 329. The reaction can be conducted in the absence ofsolvent or in a reaction inert solvent. Preferable reaction inertsolvents include aqueous media, (C₁-C₄)alcohol, (C₂C₆)glycol, ahalocarbon, an aliphatic or aromatic hydrocarbon, an ether, a polaraprotic solvent, a ketone, or combinations thereof. The reaction timeranges from 15 minutes to 3 days and the reaction temperature rangesfrom 0° C. to 180° C. or to the reflux temperature of the solvent beingused. The reactions are preferably conducted at ambient pressure.

In certain cases which will be recognized by those skilled in the art,transformations of existing functionality in Ar¹ of compound 5-3 may benecessary to produce compounds of formula 54. This pertains inparticular to those cases where, for example, R⁹ in 5-3 contains anaromatic or heteroaromatic halide, (C₁-C₄)alkylsulfonate or triflate.Said compounds of formula 5-3 wherein Ar¹ contains up to twosubstituents selected from halide, {C₁-C₄)alkylsulfonate or triflate,may be converted to a compound of formula Ar¹ where said halide,(C₁-C₄)alkylsulfonate or triflate is transformed into another functionalgroup by a reduction reaction or by a displacement reaction of saidhalide, (C₁-C₄)alkylsulfonate or triflate with a nucleophile. Thereduction reaction is conducted with a reducing agent, preferablyammonium formate or hydrogen gas, in a reaction inert solvent. Thereduction is conducted in the presence of a palladium catalyst atambient pressure or under a hydrogen pressure of up to 50 psi. Preferredsolvents include (C₁-C₄)alcohols such as methanol and ethanol, and ethersolvents such as diethyl ether, dioxane and tetrahydrofuran. Thenucleophilic displacement reaction may be conducted by adding, thenucleophile directly or by pre-forming the nucleophile separately or insitu from a nucleophile precursor. Preferred nucleophiles includeorganoaluminum, organoboron, organocopper, organotin, organozinc orGrignard reagent; R¹¹-oxide or R¹¹-thioxide; or anilino where anilino iswithin the scope of R¹¹. It will be recognized by those skilled in theart that transition-metal catalysts may be required to effect reactionin certain displacement reactions. When required, such transition metalcatalysts may include palladium(0), palladium(II), nickel(0), andnickel(II) complexes. Palladium(II) bis(diphenylphosphinobutane)dichloride is a preferred such catalyst. Additionally, an aqueous ornon-aqueous base may be required in the displacement reaction. Preferredsuch bases include sodium carbonate, sodium hydride, triethylamine andsodium tert-butoxide. The reaction is conducted at ambient pressure in areaction inert solvent such as a halocarbon, an aromatic or aliphatichydrocarbon, an ether or a polar aprotic solvent or a combinationthereof. In certain cases, a (C₁-C₄)alcohol is used as a solvent orco-solvent. The reaction temperature ranges from −20° C. to the refluxtemperature of the solvent employed. The reaction time ranges from 1hour to 3 days.

Optional protecting groups which may be present in compounds of formula5-3 are removed according to methods set forth above, or according tomethods well known to those skilled in the art, particularly as setforth in: Greene, T. W.; Wuts, P. G. M. Protective Groups in OrganicSynthesis, 2^(nd) ed.; John Wiley and Sons Inc.: New York, 1991.

Compounds of formula 54 are prepared from the displacement reaction ofamine 5-3 as described in Scheme 1, where the amine 5-3 is equivalent toR³—NH. A representative set of amines of formula 5-3 which arecommercially available or which can be prepared by a literatureprocedure include 1-phenyl-piperazine (Aldrich),1-pyridin-2-yl-piperazine (Aldrich), 3-piperazin-1-yl-benzo[d]isoxazole(J. Med. Chem. 1986, 29, 359), 3-piperazin-1-yl-benzo[d]isothiazole (J.Med. Chem. 1986, 29, 359), 2-piperazin-1-yl-quinoxaline (J. Med. Chem.1981, 24, 93), 1-naphthalen-2-yl-piperazine (cf. Tetrahedron Lett. 1994,35, 7331), and 1-(3,5-dimethylphenyl)-piperazine (cf. Tetrahedron Lett.1994, 35, 7331). Other compounds of formula 5-3 can be prepared usingmethods well known to those skilled in the art or by using methodsanalogous to those described in the foregoing references.

Alternatively, compounds of formula 54 can be prepared from reactionwith compounds of formula 5-1 with compounds of formula 5-5 usingconditions set forth above to prepare 5-3. Compounds of formula 5-5 canbe prepared in a manner analogous to the method used to preparecompounds of formula I-3.

Compounds of formula 54 wherein X is oxycarbonyl, vinylenylcarbonyl,oxy(C₁-C₄)alkylenylcarbonyl, (C₁-C₄)alkylenylcarbonyl,(C₃-C₄)alkenylcarbonyl, thio(C₁-C₄)alkenylcarbonyl, vinylenylsulfonyl orcarbonyl(C₀-C₄)alkylenylcarbonyl; wherein saidoxy(C₁-C₄)alkylenylcarbonyl, (C₁-C₄)alkylenylcarbonyl,(C₃-C₄)alkenylcarbonyl, and thio(C₃-C₄)alkenylcarbonyl in the definitionof X are each optionally and independently substituted with up to two(C₁-C₄)alkyl, benzyl, or Ar; said vinylenylsulfonyl and saidvinylenylcarbonyl in the definition of X are each optionally andindependently substituted with up to three (C₁-C₄)alkyl, benzyl, or Arare also prepared according to Scheme 5 above and particularly asdescribed below.

Compounds of formula 54 where X is as defined in the immediatelypreceding paragraph are prepared by reacting a compound of formula 5-5with a compound of formula 5-1 where R⁹ is described above, X is asdefined in the immediately preceding paragraph and Lv³ is chloro. Thereaction is conducted under anhydrous conditions in the presence of anon-aqueous base, which includes organic amines such as triethylamine,N,N′-diisopropylethylamine and pyridine and derivatives thereof. Thereaction is generally conducted in a reaction inert solvent. Preferredsolvents include halocarbon, aliphatic or aromatic hydrocarbon, ethers,ethyl acetate, pyridine and combinations thereof. The reaction timeranges from 15 minutes to 24 hours and the reaction temperature rangesfrom 0° C. to 80° C. or to the reflux temperature of the solvent beingused. The reactions are preferably conducted at from 0° C. to ambienttemperature and at ambient pressure. Removal of optional protectinggroups is carried out as described in Scheme I.

Compounds of formula 54 wherein X is vinylenylcarbonyl,oxy(C₁-C₄)alkylenylcarbonyl, (C₁-C₄)alkylenylcarbonyl,(C₃-C₄)alkenylcarbonyl, thio(Cr C₄)alkenylcarbonyl, orcarbonyl(C₀-C₄)alkylenylcarbonyl; wherein saidoxy(C₁-C₄)alkylenylcarbonyl, (C₁-C₄)alkylenylcarbonyl,(C₃-C₄)alkenylcarbonyl, and thio(C₂-C₄)alkenylcarbonyl in the definitionof X are each optionally and independently substituted with up to two(C₁-C₄)alkyl, benzyl, or Ar; and said vinylenylcarbonyl in thedefinition of X are each optionally and independently substituted withup to three (C₁-C₄)alkyl, benzyl, or Ar are also prepared according toScheme 5 avove and particularly as described below.

Compounds of formula 5-4 are prepared by reacting a compound of formula5-5 with a compound of formula R⁹-X-Lv³ where R⁹ is described above, Xis as defined in the immediately preceding paragraph and Lv³ is OH. Thereaction is conducted in the presence of coupling agents, preferablydicyclohexylcarbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride as describedin J. Amer. Chem. Soc. 1996, 118, 4952. The reaction is conducted in areaction inert solvent. Preferred solvents include halocarbon, aliphaticor aromatic hydrocarbon and ethers. Especially preferred solventsinclude dichloromethane and chloroform. Other coupling agents that canbe used are well known to those skilled in the art and include, but arenot limited to, various phosphine reagents, ethyl chloroformate, andN-hydroxysuccinimide. These reagents and procedures are described in“Compendium of Organic Synthetic Methods” (Ed., l. T. Harrison and S.Harrison, John Wiley & Sons). Specific references include the following:J. Org. Chem, 1971, 36, 1305; Bull. Soc. Chim. Fr., 1971, 3034; Bull.Chem. Soc. Japan, 1971, 44, 1373; Tetrahedron Lett., 1973, 28, 1595;Tetrahedron Lett., 1971, 26, 2967, and J. Med. Chem., 1968, 11, 534.Removal of optional protecting groups is carried out as described inScheme 1.

Compounds of formula 5-4 wherein X is a covalent bond and R⁹ is(C₃-C₇)cycloalkyl or Ar¹—(C₁-C₃)alkylenyl are also prepared according toScheme 5 above and particularly as described below.

Compounds of formula 5-4 wherein X is a covalent bond and R⁹ is(C₃-C₇)cycloalkyl or Ar¹—(C₁-C₃)alkylenyl are prepared by reacting acompound of formula 5-1 wherein X is a covalent bond, R⁹ is(C₃-C₇)cycloalkyl or Ar¹—(C₁-C₃)alkylenyl and Lv³ is halo,methanesulfonate, p-toluenesulfonate or trifluoromethanesulfonate. Thereaction is conducted under anhydrous conditions in the presence of anon-aqueous base, which includes organic amines such as triethylamine,N,N′-diisopropylethylamine and pyridine and derivatives thereof. Thereaction is conducted in a reaction inert solvent. Preferred solventsfor the reaction include halocarbons, aliphatic or aromatichydrocarbons, ethers, ethyl acetate, pyridine and combinations thereof.The reaction time ranges from 15 minutes to 24 hours and the reactiontemperature ranges from −20° C. to 80° C. or to the reflux temperatureof the solvent being used. The reactions are preferably conducted atambient temperature of the solvent being used and at ambient pressure.Removal of optional protecting groups is conducted as set forth inScheme I.

Compounds of formula 6-5 wherein G, G¹, G², q, R¹, R², R⁶R⁷ and R⁸ areas defined above are prepared as set forth in Scheme 6 above andparticularly as described below.

Compounds of formula 6-1 are prepared from an amine of the formula 5-2where Prt is an optional amine protecting group selected from benzyl andCO₂R⁹⁰, where R⁹⁰ is selected from (C₁-C₄)alkyl, (C₁-C₄)alkyl,trichloroethyl and benzyl substituted with up to two (C₁-C₄)alkoxy. Thepreferred procedure for preparing compounds of formula 6-1 can be foundin Tetrahedron Lett. 1993, 48, 7767 or J. Org. Chem 1997, 62, 1540.

Compounds of formula 6-3 are prepared by condensation of β-diketones orβ-ketoesters of the formula 6-2b, where R¹¹ and R¹² are independentlysubstituted as set forth above, or compounds of the formula 6-2a where Lis, for example, hydroxy, chloro or dimethylamino with guanidines of theformula 6-1. The reaction is conducted in the presence of an aqueous ornon-aqueous base, preferably potassium, or sodium hydroxide, potassiumor sodium (C₁-C₄)alkoxide, thiethylamine, pyridine,4-dimethylaminopyridine, potassium or sodium carbonate or potassium orsodium bicarbonate. The reaction is conducted in a, reaction inertsolvent, preferably aqueous media, a (C₁-C₄)alcohol, a (C₂-C₆)dialcohol,an aromatic hydrocarbon, a polar aprotic solvent, or combinationsthereof. The reaction time ranges from 2 hours to 3 days and thereaction temperature ranges from room temperature to reflux of thesolvent employed. The reaction is preferably run at ambient pressure,but may be conducted at, pressures up to 250 psi.

Removal of of optional protecting groups in compounds of formula 6-3 toafford compounds of formula 64 is accomplished as set forth above.

Compounds of, formula 6-5 are prepared from the displacement reaction ofamine 64 as described in Scheme 1, where the amine 64 is equivalent toR³NH.

Alternatively, compounds of formula 6-5 are prepared from compounds offormula 5-5 by formation of a compound of formula 66, or by reactionwith compounds of formula 6-2a or 6-2b under the conditions outlinedabove in Scheme 6.

Removal of optional protecting groups is conducted as described inScheme 1. Compounds of formula 5-5 are prepared as set forth above.

Compounds of formula 7-4 wherein G³, G⁴, G⁵, r, R¹, R², R¹⁸, R¹⁹ and R²⁰are defined as set forth above are prepared as set forth in Scheme 7 andparticularly as described below.

Compounds of formula 7-1 are prepared by reaction of an amine of theformula 7-0 with phosgene or a phosgene equivalent such as triphosgene.Compounds of 7-1 wherein the chloro group is replaced by an imidazolylgroup are also useful in this reaction. Such compounds are prepared byreaction of an amine of formula 7-0 with carbonyl diimidazole. Thereaction is conducted under anhydrous conditions in the presence of anonaqueous base. Preferred such bases include triethylamine and othertertiary amines and pyridine and derivatives thereof. The reaction isconducted in a reaction inert solvent at −78° C. to 80° C. or at thereflux temperature of the solvent being used for 15 minutes to 24 hours.Preferred solvents for this reaction include a halocarbon, an aliphaticor aromatic hydrocarbon, an ether, ethyl acetate, pyridine andcombinations thereof. The reactions are preferably conducted at from 0°C. to ambient temperature and at ambient pressure.

Compounds of formula 74 are prepared by reaction of carbamoyl chloridesof the formula 7-1 with amines of the formula 7-3, where R²¹ and R²² aredefined above. The reaction can be conducted in the absence of solvent,or in a reaction inert solvent. Preferred such solvents include aqueousmedia, a (C₁-C₄)alcohol, a (C₂-C₆)dialcohol, an aromatic or aliphatichydrocarbon, a halocarbon, an ether, a polar aprotic solvent, a, ketone,pyridine or combinations thereof. The reaction time ranges from 15minutes to 3 days and the reaction temperature ranges from 0° C. to thereflux temperature of the solvent being used. The reaction is preferablyconducted at ambient pressure. It will be recognized by those skilled inthe art that addition of a base may be required to effect reaction. Inthose cases, preferred bases include potassium or sodium hydroxide,triethylamine and other tertiary amines, pyridine and its derivativesand inorganic bases such as sodium or potassium carbonate and sodium orpotassium bicarbonate. Removal of optional hydroxyl protecting groupscontained in R¹ is carried out according to methods set forth in Scheme1.

Alternatively, compounds of formula 74 are prepared from compounds offormula 7-0 by reaction with isocyanates of the formula 74 or withcarbamoyl chlorides of the formula 7-8. Said isocyanates arecommercially available, known in the literature, or synthesized understandard conditions known to those skilled in the art, particularly asdescribed in March, J. Advanced Organic Chemistry, 3^(rd) ed.; JohnWiley and Sons Inc.: New York, 1985, p 1166. A preferred method offorming such isocyanates is the Curtius rearrangement of a suitable acylazide. Said carbamoyl chlorides are synthesized using methods analogousto that described for the preparation of compounds of formula 7-1 inScheme 7. Removal of optional hydroxyl protecting groups contained in R¹is carried out according to methods set forth in Scheme 1.

Compounds of formula I containing the radical R³ are prepared accordingto the procedures set forth in Scheme 7 using the corresponding startingmaterials and reagents.

Compounds of formula 8-5 are prepared as set forth in Scheme 8 andparticularly as described below.

Compounds of formula 8-2 are readily prepared from commerciallyavailable phenethylamines of formula 8-1a and formaldehyde or analdehyde of the formula R²⁷—CHO under Pictet-Spengler conditions. ThePictet-Spengler reaction is reviewed in Chem. Rev. 1995, 95, 1797. Asimilar route route to 1,2,3,4-tetrahydroisoquinolines using theBischler-Napieralski reaction, as disdosed in March, J. Advanced OrganicChemistry, 3^(rd) ed.; John Wiley and Sons.: New York, 1985, 495,followed by standard reduction of the imine formed may also be employed.

Compounds of formula 84 are prepared from compounds of formula 8-3 byaromatic electrophilic substitution using the appropriate electrophile.A general reference for this type of reaction can be found in March, J.Advanced Organic Chemistry, 3^(rd) ed.; John Wiley and Sons.: New York,1985, 447-511.

Compounds of formula 8-2 are also prepared by removal of the protectinggroup from a compound of formula 84. Preferably the protecting group istrifluoroacetamide which may be removed under basic conditions usinginorganic hydroxides or carbonates in a reaction inert solvent. Suitablesuch solvents include (C₁-C₄)alcohols and preferably methanol.Optionally, one or more co-solvents, preferably selected from water,tetrahydrofuran and dioxane may be employed. The reaction time rangesfrom 15 minutes to 24 hours and the reaction temperature ranges from 0°C. to 100° C. or to the reflux temperature of the solvent or solventsystem being used. The reaction is preferably conducted at ambienttemperature. Other conditions for deprotection of trifluoroacetamidesand deprotection conditions for other suitable protecting groups can befound in Greene, T. W.; Wuts, P. G. M. Protective Groups in OrganicSynthesis, 2^(nd) ed.; John Wiley and Sons Inc.: New York, 1991.

Compounds of formula 84 are prepared by adding a protecting group tocompounds of formula 8-2. Preferably the protecting group istrifluoroacetamide or tert-butoxycarbonyl (BOC). The protecting group isattached by reaction of a compound of formula 8-2 with trifluoroacetylchloride or di-tert-butyl dicarbonate or an equivalent thereof in thepresence of a base, preferably triethylamine or pyridine. The reactionis conducted in a reaction inert solvent. Preferred such solventsinclude ethers such as tetrahydrofuran, diethyl ether, dioxane ordimethoxyethane; a halocarbon such as dichloromethane, chloroform orcarbon tetrachloride; and aromatic or aliphatic hydrocarbons such asbenzene, toluene or hexanes. The reaction time ranges from 15 minutes to3 days and the reaction temperature ranges from 0° C. to the refluxtemperature of the solvent being used. The reaction is preferablyconducted at ambient pressure. Other conditions for protection of amineswith trifluoroacetamides or tert-butoxycarbonyl groups as well as othersuitable protecting groups can be found in Greene, T. W.; Wuts, P. G. M.Protective Groups in Organic Synthesis, 2^(nd) ed.; John Wiley and SonsInc.: New York, 1991.

Manipulation of the substituents R²⁸ and R²⁹ is carried out to provideisoquinolines with altered substitution. Preferably, transitionmetal-catalyzed cross-coupling of a compound of formula 84 where R²⁸ orR² is bromide or triflate is employed to afford compounds of formula 84wherein R² or R²⁹ are as set forth above. This reaction is conductedaccording to methods well known to those skilled in the art,particularly as set forth in Tetrahedron, 1998, 54, 263 for Stille andSuzuki Reactions and in Acc. Chem. Res. 1998, 31, 805 for BuchwaldAmination Reactions.

Compounds of formula 8-5 are prepared from the displacement reaction ofamine 8-2 as described, in Scheme 1, where the amine 8-2 is equivalentto R³—NH.

Compounds of formula 9-3 are prepared according to the generalprocedures set forth in Scheme 2 starting from ethyl1-benzyl-4-oxo-3-piperidine carboxylate hydrochloride (9-1). In certaincases, where R²⁹ is H,N-tertbutoxycarbonyl-3-(dimethylaminomethylene)₄-piperidone (9-2,Chemical Abstracts 121:157661) is used as the starting material.

Compounds of formula 10-6 wherein R¹, R²R³² and R³³ are as defined aboveare prepared as set forth in Scheme 10 and more particularly asdescribed below.

Compounds of formula 10-2 where R⁹¹ is (C₁-C₄)alkyl are prepared byreacting a compound of formula 10-1, where Cbz is benzyloxycarbonyl,with an O-alkylating agent. A preferred compound of formula 10-1 is3-oxo-piperazine-1-carboxylic acid benzyl ester. A preferredO-alkylating agent is triethyloxonium tetrafluoroborate. The reaction isconducted at ambient pressure in a reaction inert solvent. Preferredsolvents include an aromatic or aliphatic hydrocarbons, halocarbons andethers. Dichloromethane is especially preferred. The reaction timeranges from 2 hours to 3 days and the reaction temperature ranges from−100° C. to ambient temperature.

Compounds of formula 10-4 are prepared by condensation of a compound offormula 10-2 with a compound of formula 10-3. Said compounds of formula10-3 are commercially available, are known in the literature, or arereadily prepared via standard amidation of hydrazine and an activatedcarboxylic acid, such as a carboxylic acid chloride. Such reactions arewell known by those skilled in the art. The condensation reaction ispreferably run at ambient pressure, although higher pressures up to 250psi may be employed if necessary. The reaction is conducted in areaction inert solvent, preferably selected from (C₁-C₄)alcohols,aromatic or aliphatic hydrocarbons, polar aprotic media, halocarbons andethers, or combinations thereof. The reaction is conducted attemperatures ranging from ambient temperature to 180° C. The reactiontimes are from 2 hours to 3 days.

Compounds of formula 10-5 are prepared form compounds of formula 10-4via Lewis acid-catalyzed cleavage or hydrogenolysis of the Cbz carbamateunder standard conditions which are well known to those skilled in theart, particularly as set forth in Greene, T. W.; Wuts, P. G. M.Protective Groups in Organic Synthesis, 2 ed.; John Wiley and Sons Inc.:New York, 1991, pp 335-338.

Compounds of formula 10-6 are prepared from the displacement reaction ofan amine of the formula 10-5 as described in Scheme 1, where the amine10-5 is equivalent to R³—NH.

Compounds of formula 11-4, wherein R¹, R², R³⁶, R³⁷, R³⁸, R³⁹ and R⁴⁰are as defined above are prepared as set forth in Scheme 11 and moreparticularly as described below.

Where R³⁸ and R³⁹ are hydrogen, 1-benzyl-4-piperidone (3-1), availablefrom Aldrich, is condensed with a compound of formula 11-1, which areeither commercially available or well known to those skilled in the art,to give compounds of formula 11-2. Where R³⁸ and R³⁹ are not hydrogen,compounds of formula 3-1 can, be prepared according to methods wellknown to those skilled in the art. The reaction is conducted at ambientpressure in the absence of solvent or in a reaction inert solvent.Preferred solvents include (C₁-C₄)alcohols, aromatic or aliphatichydrocarbons, polar aprotic solvents, halocarbons and ethers. Thereaction time ranges from 2 hours to 3 days and the reaction temperatureranges from ambient temperature to the reflux temperature of the solventbeing employed. More specific conditions can be found in Indian J. Chem.1976, 14B, 984 and J. Chem. Soc. Perkin Trans. 11984, 2465.

Compounds of formula 11-3 are prepared by removal of the benzylprotecting group from a compound of formula 11-2 in a manner analogousto the method employed for the preparation of compounds of 2-6 describedabove.

Compounds of formula 11-4 are prepared by the displacement reaction ofan amine of the formula 11-3 as described in Scheme 1, where the amine11-3 is equivalent to R³—H.

Compounds of formula 12-3 and 12-3a where R¹⁷ and R²³ are(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylcarbonyl, Ar²-carbonyl,(C₁-C₆)alkylsulfonyl, Ar²-sulfonyl, or Ar²-sulfinyl are preparedaccording to Scheme 12 above and particularly as set forth below.

Compounds of formula 12-3 and 12-3a where R¹⁷ and R²³ are as defined inthe immediately preceding paragraph are prepared by condensation with acompound of formula 12-2 and 12-2a, wherein Lv⁴ is chloro, respectively.Examples of compounds of formula 12-2 and 12-2a include(C₁-C₆)alkoxyCOCl, (C₁-C₆)alkylCOCl, Ar²—COCl, (C₁-C₆)alkylSO₂Cl,Ar²—SO₂Cl, or Ar²—SOCl. The reaction is conducted under anhydrousconditions in the presence of a non-aqueous base, which includes organicamines such as triethylamine, N,N′-diisopropylethylamine and pyridineand derivatives thereof. The reaction is conducted in a reaction inertsolvent. Preferred solvents or the reaction include halocarbon,aliphatic or aromatic hydrocarbon, ethers, ethyl acetate, pyridine andcombinations thereof. The reaction time ranges from 15 minutes to 24hours and the reaction temperature ranges from 0° C. to 80° C. or to thereflux temperature of the solvent being used. The reactions arepreferably conducted at from 0° C. to ambient temperature and at ambientpressure. Removal of optional protecting groups is carried out asdescribed in Scheme I.

Compounds of formula 12-3 and 12-3a wherein R¹⁷ and R²³ are(C₁-C₆)alkylcarbonyl or Ar²-carbonyl are also prepared according toScheme 12 above and particularly as described below.

Compounds of formula 12-3 and 12-3a wherein R¹⁷ and R²³ are(C₁-C₆)alkylcarbonyl or Ar²-carbonyl are prepared by a condensationreaction with a compound of formula 12-2 or 12-2a, respectively, whereinLv⁴ is hydroxy in the presence of coupling agents such asdicyclohexylcarbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Thereaction is conducted in a reaction inert solvent. Preferred solventsinclude halocarbon, aliphaticlaromatic hydrocarbons and ethers.Especially preferred solvents include dichloromethane and chloroform.Other coupling agents that can be used are well known to those skilledin the art and include, but are not limited to, various phosphinereagents, ethyl chloroformate, and N-hydroxysuccinimide. Removal ofoptional protecting groups is carried out as described in Scheme I.

Compounds of formula 12-3 where R¹⁷ is (C₁-C₆)alkyl are also preparedaccording to Scheme 12 and particularly as described below.

Compounds of formula 12-3 where R¹⁷ is (C₁-C₆)alkyl are prepared byreacting a compound of formula 12-1 with a compound of formula 12-2where R¹⁷ is (C₁-C₄)alkyl and Lv⁴ is Cl, Br, I, methanesulfonyloxy,p-toluenesulfonyloxy or trifluoromethanesulfonyloxy. The reaction isconducted under anhydrous conditions in the presence of a nonaqueousbase, which includes organic amines such as triethylamine, Hunig's baseand pyridine and derivatives thereof. The reaction is conducted in areaction inert solvent. Preferred solvents for the reaction includehalocarbons, aliphatic or aromatic hydrocarbons, ethers, ethyl acetate,pyridine and combinations thereof. The reaction time ranges from 15minutes to 24 hours and the reaction temperature ranges from ambienttemperature to 80° C. or to the reflux temperature of the solvent beingused. The reactions are preferably conducted at ambient temperature andpressure.

The starting materials and reagents for the above described compoundsare also readily available or can be easily synthesized by those skilledin the art using conventional methods of organic synthesis. For example,many of the compounds used herein are related to, or are derived fromcompounds found in nature, in which there is a large scientific interestand commercial need and accordingly many such compounds are commerciallyavailable or are reported in the literature or are easily prepared fromother commonly available substances by methods which are reported in theliterature.

The compounds of the instant invention inhibit the formation of sorbitoldehydrogenase and as such have utility in the treatment of diabeticcomplications including but not limited to such complications asdiabetic nephropathy, diabetic neuropathy, diabetic retinopathy,diabetic microangiopathy and diabetic macroangiopathy and diabeticcardiomyopathy. The utility of the compounds of the present invention asmedical agents in the treatment of diseases, such as are detailed hereinin mammals (e.g., humans) for example, diabetic complications such asdiabetic cardiomyopathy, diabetic neuropathy, diabetic nephropathy,diabetic retinopathy, diabetic microangiopathy and diabeticmacroangiopathy is demonstrated by the activity of the compounds offormula I of this invention in conventional assays. Such assays alsoprovide a means whereby the activities of the compounds of formula I ofthis invention can be compared with the activities of other knowncompounds. The results of these comparisons are useful for determiningdosage levels in mammals, including humans, for the treatment of suchdiseases.

Measurement of SDH Activity

Male Sprague-Dawley rats (350-400 g) are used for these experiments.Diabetes is induced in some of the rats by a tail vein injection ofstreptozocin, 85 mg/kg. Twenty-four hours later, 4 groups of diabeticrats are given a single dose of the test compound of formula I of thisinvention (0.001 to 100 mg/kg) by oral gavage. Animals are sacrificed4-6 hours after dosing and blood and sciatic nerves are harvested.Tissues and cells are extracted with 6% perchloric acid.

Sorbitol in erythrocytes and nerves is measured by a modification of themethod of R. S. Clements et al. (Science, 166: 1007-8,1969). Aliquots oftissue extracts are added to an assay system which has finalconcentrations of reagents of 0.033 M glycine, pH 9.4, 800 mM β-nicotineadenine dinucleotide, and 4 units/ml of sorbitol dehydrogenase. Afterincubation for 30 minutes at room temperature, sample fluorescence isdetermined on a fluorescence spectrophotometer with excitation at 366 nmand emission at 452 nm. After subtracting appropriate blanks, the amountof sorbitol in each sample is determined from a linear regression ofsorbitol standards processed in the, same manner as the tissue extracts.

Fructose is determined by a modification of the method described by M.Ameyama, Methods in Enzymology, 89: 20-25 (1982). Resazurin issubstituted for ferricyanide. Aliquots of tissue extracts are added tothe assay system, which has final concentrations of reagents of 1.2 Mcitric acid, pH 4.5, 13 mM resazurin, 3.3 units/ml of fructosedehydrogenase and 0.068% Triton X-100. After incubation for 60 minutesat room temperature, sample fluorescence is determined on a fluorescencespectrophotometer with excitation at 560 nm and emission at 580 nm.After, subtracting appropriate blanks, the amount of fructose in eachsample is determined from a linear regression of fructose standardsprocessed in the same manner as the tissue extracts.

SDH activity is measured by a modification of the method described by U.Gerlach, Methodology of Enzymatic Analyses, edited by H. U. Bergmeyer,3, 112-117 (1983). Aliquots of sera or urine are added to the assaysystem, which has final concentrations of reagents of 0.1 M potassiumphosphate buffer, pH 7.4, 5 mM NAD, 20 mM sorbitol, and 0.7 units/ml ofsorbitol dehydrogenase. After incubation for 10 minutes at roomtemperature, the average change in sample absorbance is determined at340 nm. SDH activity was presented as milliOD₃₄₀ units/minute(OD₃₀=optical density at 340 nm).

Any aldose reductase inhibitor may be used as the second compound(active agent) of this invention for combination therapies. The termaldose reductase inhibitor refers to compounds which inhibit thebioconversion of glucose to sorbitol catalyzed by the enzyme aldosereductase. Such inhibition is readily determined by those skilled in theart according to standard assays (J. Malone, Diabetes, 29:861-864, 1980.“Red Cell Sorbitol, an Indicator of Diabetic Control”). A variety ofaldose reductase inhibitors are described and referenced below, however,other aldose reductase inhibitors will be known to those skilled in theart. The disclosures of U.S. patents listed below are herebyincorporated by reference. Also, common chemical USAN names or otherdesignation are in parentheses where applicable, together with referenceto appropriate patent literature disclosing the compound.

The activity of an aldose reductase inhibitor in a tissue can bedetermined by testing the amount of aldose reductase inhibitor that isrequired to lower tissue sorbitol (i.e., by inhibiting the furtherproduction of sorbitol consequent to blocking aldose reductase) of lowertissue fructose (by inhibiting the, production of sorbitol consequent toblocking aldose reductase and consequently the production of fructose).While not wishing to be bound by any particular theory or mechanism, itis believed that an aldose reductase inhibitor, by inhibiting aldosereductase, prevents or reduces ischemic damage as described hereinafter.

Accordingly, examples of aldose reductase inhibitors useful in thecompositions and methods of this invention including:

-   -   1.        3-(4-bromo-2-fluorobenzyl)-3,4-dihydro-4-oxo-1-phthalazineacetic        acid (ponalrestat, U.S. Pat. No. 4,251,528);    -   2.        N[[(5-trifluoromethyl)-6-methoxy-1-naphthalenyl]thioxomethyl}-N-methylglycine        (tolrestat, U.S. Pat. No. 4,600,724);    -   3.        5-[(Z,E)-β-methylcinnamylidene]4-oxo-2-thioxo-3-thiazolideneacetic        acid (epalrestat, U.S. Pat. No. 4,464,382, U.S. Pat. No.        4,791,126, U.S. Pat. No. 4,831,045);    -   4.        3-(4-bromo-2-fluorobenzyl)-7-chloro-3,4-dihydro-2,4-dioxo-112H)-quinazolineacetic        acid (zenarestat, U.S. Pat. Nos. 4,734,419, and 4,883,800);    -   5. 2R,4R-6,7-dichloro-4-hydroxy-2-methylchroman-4-acetic acid        (U.S. Pat. No. 4,883,410);    -   6.        2R,4R-6,7-dichloro-6-fluoro-4-hydroxy-2-methylchroman-4-acetic        acid (U.S. Pat. No. 4,883,410);    -   7. 3,4-dihydro-2,8-diisopropyl-3-oxo-2H-1,4-benzoxazine-4-acetic        acid (U.S. Pat. No. 4,771,050);    -   8.        3,4-dihydro-3-oxo-4-[(4,5,7-trifluoro-2-benzothiazolyl)methyl]-2H-1,4-benzothiazine-2-acetic        acid (SPR-210, U.S. Pat. No. 5,252,572);    -   9.        N-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl}-2-methyl-benzeneacetamide        (ZD5522, U.S. Pat. No. 5,270,342 and U.S. Pat. No. 5,430,060);    -   10. (S)-6-fluorospiro[chroman-4,4′-imidazolidine]-2,5′-dione        (sorbinil, U.S. Pat. No. 4,130,714);    -   11.        d-2-methyl-6-fluoro-spiro(chroman-4,4′-imidazolidine)-2′,5′-dione        (U.S. Pat. No. 4,540,704);    -   12. 2-fluoro-spiro 9H-fluorene-9,4′-imidazolidine)-2′,5′-dione        (U.S. Pat. No. 4,438,272);    -   13.        2,7-di-fluoro-spiro(9H-fluorene-9,4′-imidazolidine)-2′,5′-dione        (U.S. Pat. No. 4,436,745, U.S. Pat. No. 4,438,272);    -   14.        2,7-di-fluoro-5-methoxy-spiro(9H-fluorene-9,4′-imidazolidine)-2′,5′-dione        (U.S. Pat. No. 4,436,745, U.S. Pat. No. 4,438,272);    -   15.        7-fluoro-spiro(5H-indenol[1,2-b]pyridine-5,3′-pyrrolidine)-2,5′-dione        (U.S. Pat. No. 4,436,745, U.S. Pat. No. 4,438,272);    -   16.        d-cis-6′-chloro-2′,3′-dihydro-2′-methyl-spiro-(imidazolidine-4,4′-4′,H-pyrano(2,3-b)pyridine)-2,5-dione        (U.S. Pat. No. 4,980,357);    -   17.        spiro[imidazolidine-4,5′(6H)-quinoline]-2,5-dione-3′-chloro-7′,8′-,        dihydro-7′-methyl-(5′-cis) (U.S. Pat. No. 5,066,659);    -   18.        (2S,4S)-6-fluoro-2′,5′-dioxospiro(chroman-4,4′-imidazolidine)-2-carboxamide        (U.S. Pat. No. 5,447,946); and    -   19.        2-[(4-bromo-2-fluorophenyl)methyl]-6-fluorospiro[isoquinoline-4(1H),3′-pyrrolidine]-1,2′,3,5′(2H)-tetrone        (ARI-509, U.S. Pat. No. 5,037,831).

Other aldose reductase inhibitors include compounds having formula ARI,

or a pharmaceutically acceptable salt thereof, wherein

-   -   Z in the compound of formula ARI is O or S;    -   R¹ in the compound of formula ARI is hydroxy or a group capable        of being removed in vivo to produce a compound of formula ARI        wherein R¹ is OH; and    -   X and Y in the compound of formula ARI are the same or different        and are selected from hydrogen, trifluoromethyl, fluoro, and        chloro.

A preferred subgroup within the above group of aldose reductaseinhibitors includes numbered compounds 1, 2, 3, 4, 5, 6, 9, 10, and 17,and the following compounds of Formula ARI:

-   -   20.        3,4-dihydro-3-(5-fluorobenzothiazol-2-ylmethyl)4-oxophthalazin-1-yl-acetic        acid [R¹=hydroxy; X=F; Y=H];    -   21. 3        (5,7-difluorobenzothiazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1        ylacetic acid [R¹=hydroxy; X=Y=F];    -   22.        3-(5-chlorobenzothiazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylacetic        acid, [R¹=hydroxy; X=Cl; Y=H];    -   23.        3-(5,7-dichlorobenzothiazol-2-ylethyl)-3,4-dihydro-4-oxophthalazin-1-ylacetic        acid [R¹=hydroxy; X=Y=Cl];    -   24.        3,4-dihydro-4-oxo-3-(5-trifluoromethylbenzoxazol-2-ylmethyl)phthalazin-1-ylacetic        acid [R¹=hydroxy; X=CF₃; Y=H];    -   25.        3,4-dihydro-3-(5-fluorobenzoxazol-2-ylmethyl)₄-oxophthalazin-1-yl-acetic        acid [R¹=hydroxy; X=F; Y=H];    -   26.        3-(5,7-difluorobenzoxazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylacetic        acid [R¹=hydroxy; X=Y=F];    -   27.        3-(5-chlorobenzoxazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylacetic        acid [R¹=hydroxy; X=Cl; Y=H];    -   28.        3-(5,7-dichlorobenzoxazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylacetic        acid [R¹=hydroxy; X=Y=Cl]; and    -   29. zopolrestat; 1-phthalazineacetic acid,        3,4-dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl]methyl]-[R¹=hydroxy;        X=trifluoromethyl; Y=H].

In compounds 20-23, and 29 Z is S. In compounds 24-28, Z is 0.

Of the above subgroup, compounds 20-29 are more preferred with 29especially preferred.

An especially preferred aldose reductase inhibitor is1-phthalazineacetic acid,3,4-dihydro-4-oxo-3-[[5-trifluoromethyl)-2-benzothiazolyl]methyl]-.

The term “acyl radical of a carboxylic acid aldose reductase inhibitor”refers to any of the above-mentioned aldose reductase inhibitors whichcontains a carboxylic acid group in which the carboxylic acid group isreplaced with a carbonyl radical.

The aldose reductase inhibitor compounds of this invention are readilyavailable or can be easily synthesized by those skilled in the art usingconventional methods of organic synthesis, particularly in view of thepertinent patent specification descriptions.

An amount of the aldose reductase inhibitor of this invention that iseffective for the activities of this invention may be used. Typically,an effective dosage for the aldose reductase inhibitors of thisinvention is in the range of about 0.1 mg/kg/day to 100 mg/kg/day insingle or divided doses, preferably 0.1 mg/kg/day to 20 mg/kg/day insingle or divided doses.

Any sodium hydrogen ion exchange (NHE-1) inhibitor may be used as thesecond compound (active agent) of this invention for combinationtherapies. The term NHE-1 inhibitor refers to compounds which inhibitthe sodium/proton (Na⁺/H⁺) exchange transport system and hence areuseful as ae therapeutic or prophylactic agent for diseases caused oraggravated by the acceleration of the sodium/proton (Na⁺/H⁺) exchangetransport system, for example, cardiovascular diseases [e.g.,arteriosclerosis, hypertension, arrhythmia (e.g. ischemic arrhythmia,arrhythmia due to myocardial infarction, myocardial stunning, myocardialdysfunction, arrhythmia after PTCA or after thrombolysis, etc.), anginapectoris, cardiac hypertrophy, myocardial infarction, heart failure(e.g. congestive heart failure, acute heart failure, cardiachypertrophy, etc.), restenosis after PTCA, PTCI, shock (e.g. hemorrhagicshock, endotoxin shock, etc.)], renal diseases (e.g. diabetes mellitus,diabetic nephropathy, ischemic acute renal failure, etc.) organdisorders associated with ischemia or ischemic reperfusion [e.g. heartmuscle ischemic reperfusion associated, disorders, acute renal failure,or disorders induced by surgical treatment such as coronary arterybypass grafting (CABG) surgeries, vascular surgeries, organtransplantation, non-cardiac surgeries or percutaneous transluminalcoronary angioplasty (PTCA)], cerebrovascular diseases (e.g. ischemicstroke, hemorrhagic stroke, etc.), cerebro ischemic disorders (e.g.disorders associated with cerebral infarction, disorders caused aftercerebral apoplexy as sequelae, or cerebral edema. NHE-1 inhibitors canalso be used as an agent for myocardial protection during coronaryartery bypass grafting (CABG) surgeries, vascular surgeries,percutaneous transluminal coronary angioplasty (PTCA), PTCI, organtransplantation, or non-cardiac surgeries. The utility of NHE-1inhibitors as medical agents in the treatment of diseases, such as aredetailed herein in mammals (e.g. humans) for example, myocardialprotection during surgery or mycardial protection in patients presentingwith ongoing cardiac or cerebral ischemic events or chroniccardioprotection in patients with diagnosed coronary heart disease, orat risk for coronary heart disease, cardiac dysfunction or myocardialstunning is demonstrated by the activity of the compounds of formula Iof this invention in conventional preclinical cardioprotection assays[see the in vivo assay in Klein, H. et al., Circulation 92:912-917(1995); the isolated heart assay in Scholz, W. et al., CardiovascularResearch 29:260-268 (1995); the antiarrhythmic assay in Yasutake M. etal., Am. J. Physiol., 36:H2430-H2440 (1994); the NMR assay in Kolke etal., J. Thorac. Cardiovasc. Surg. 112: 765-775 (1996)] and theadditional in vitro and in vivo assays described below. Such assays alsoprovide a means whereby the activities of the compounds of formula I ofthis invention can be compared with the activities of other knowncompounds. The results of these comparisons are useful for determiningdosage levels in mammals, including humans, for the treatment of suchdiseases.

NHE-1 inhibitors are disclosed in U.S. Pat. No. 5,698,581, EuropeanPatent Application Publication No. EP 803 501 A1, International PatentApplication Publication Nos. WO 94/26709 and PCT/JP97/04650, each ofwhich is incorporated herein by reference. The NHE-1 inhibitorsdisclosed therein have utility in the combination of this invention.Said NHE-1 inhibitors can be prepared as disclosed therein. PI

Preferred NHE-1 inhibitors include compounds of the formula NHE,

a prodrug thereof or a pharmaceutically acceptable salt of said compoundor of said prodrug, wherein

-   -   Z in the compound of formula NHE is carbon connected and is a        five-membered, diaza, diunsaturated ring having two contiguous        nitrogens, said ring optionally mono-, di-, or tri-substituted        with up to three substituents independently selected from R¹, R²        and R³; or    -   Z in the compound of formula NHE carbon connected and is a        five-membered, triaza, diunsaturated ring, said ring optionally        mono- or di-substituted with up to two substituents        independently selected from R⁴ and R⁵;    -   wherein R¹, R², R³, R⁴ and R⁵ in the compound of formula NHE are        each independently hydrogen, hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl,        (C₁-C₄)alkylthio, (C₃-C₄)cycloalkyl,        (C₃-C₇)cycloalkyl(C₁-C₄)alkyl, (C₁-C₄)alkoxy,        (C₁-C₄)alkoxy(C₁-C₄)alkyl, mono-N— or        di-N,N—(C₁-C₄)alkylcarbamoyl, M or M(C₁-C₄)alkyl, any of said        previous (C₁-C₄)alkyl moieties optionally having from one to        nine fluorines; said (C₁-C₄)alkyl or (C₃-C₄)cycloalkyl        optionally mono-or di-substituted independently with hydroxy,        (C₁-C₄)alkoxy, (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl,        (C₁-C₄)alkylsulfonyl, (C₁-C₄)alkyl, mono-N— or        di-N,N—(C₁-C₄)alkylcarbamoyl or mono-N— or        di-N,N-(C₁-C₄)alkylaminosulfonyl; and said (C₃-C₄)cycloalkyl        optionally having from one to seven fluorines;    -   wherein M in the compound of formula NHE is a partially        saturated fully saturated or fully unsaturated five to eight        membered ring optionally having one to three heteroatoms        selected independently from oxygen, sulfur and nitrogen, or, a        bicyclic ring consisting of two fused partially saturated, fully        saturated or fully unsaturated three to six membered rings,        taken independently, optionally having one to four heteroatoms        selected independently from nitrogen, sulfur and oxygen;    -   said M in the compound of formula NHE is optionally substituted,        on one ring if the moiety is monocyclic, or one or both rings if        the moiety is bicyclic, on carbon or nitrogen with up to three        substituents independently selected from R⁶, R⁷ and R⁸, wherein        one of R⁶, R⁷ and R⁸ is optionally a partially saturated, fully        saturated, or fully unsaturated three to seven membered ring        optionally having one to three heteroatoms selected        independently from oxygen, sulfur and nitrogen optionally        substituted with (C₁-C₄)alkyl and additionally R⁶, R⁷ and R⁸ are        optionally hydroxy, nitro, halo, (C₁-C₄)alkoxy,        (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, formyl, (C₁-C₄)alkanoyl,        (C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino,        (C₁-C₄)alkoxycarbonylamino, sulfonamido,        (C₁-C₄)alkylsulfonamido, amino, mono-N— or        di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— or        di-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₄)alkylthio,        (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl, mono-N— or        di-N,N—(C₁-C₄)alkylaminosulfonyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl        or (C₅-C₇)cycloalkenyl,    -   wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl, (C₁-C₇)alkanoyl,        (C₁-C₄)alkylthio, mono-N— or di-N,N—(C₁-C₄)alkylamino or        (C₃-C₇)cycloalkyl R⁶, R⁷ and R⁸ substituents are optionally        mono-substituted independently with hydroxy,        (C₁-C₄)alkoxycarbonyl, (C₃-C₇)cycloalkyl, (C₁-C₄)alkanoyl,        (C₁-C₄)alkanoylamino, (C₁-C₄)alkanoyloxy,        (C₁-C₄)alkoxycarbonylamino, sulfonamido,        (C₁-C₄)alkylsulfonamido, amino, mono-N— or        di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— or        di-N,N-(C₁-C₄)alkylcarbamoyl, cyano, thiol, nitro,        (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or        mono-N— or di-N,N—(C₁-C₄)alkylaminosultfonyl or optionally        substituted with one to nine fluorines.

Especially preferred NHE-1 inhibitors include[1-(8-bromoquinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;[1-(6-chloroquinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;[1 (indalzol-7-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;[1-(benzimidazol-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;[1′-(1-isoquinolyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;[5-cyclopropyl-1-(4-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine;[5-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carbonyl]guanidine;[5-cyclopropyl-1-(quinolin-8-yl)-1H-pyrazole-4-carbonyl]guanidine;[1-(indazol-6-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;[1-(indazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;[1-(benzimidazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guianidine;[1-(1-methylbenzimidazol-6-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;1-(5-quinolinyl)-5-n-propyl-1H-pyrazole-carbonyl]guanidine;[1-(5-quinolinyl)-5-isopropyl-1H-pyrazole-4-carbonyl]guanidine;(5-ethyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine;[1-(2-methylbenzimidazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;[1-(1,4-benzodioxan-6-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;[1-(benzotriazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;[1-(3-chloroindazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;[1-(5-quinolinyl)-5-butyl-1H-pyrazole-4-carbonyl]guanidine;[5-propyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine;[5-isopropyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine;[1-(2-chloro-4-methylsulfonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;[1-(2-chlorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;[1-(2-trifluoromethyl-4-fluorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;[1-(2-bromophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;[1-(2-fluorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;[1-(2-chloro-5-methoxyphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;[1-(2-chloro-4-methylaminosulfonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;[1-(2,5-dichlorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;[1-(2,3-dichlorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;[1-(2-chloro-5-aminocarbonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;[1-(2-chloro-5-aminosulfonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;[1-(2-fluoro-6-trifluoromethylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;[1-(2-chloro-5-methylsulfonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;[1-(2-chloro-5-dimethylaminosulfonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;[1-(2-trifluoromethyl-4-chlorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;[1-(2-chlorophenyl)-5-methyl-1H-pyrazole-4-carbonyl]guanidine;[5-methyl-1-(2-trifluoromethylphenyl)-1H-pyrazole-4-carbonyl]guanidine;[5-ethyl-1-phenyl-1H-pyrazole-4-carbonyl]guanidine;[5-cyclopropyl-1-(2-trifluoromethylphenyl)-1H-pyrazole-4-carbonyl]guanidine;[5-cyclopropyl-1-phenyl-1H-pyrazole-4-carbonyl]guanidine;[5-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazole-4-carbonyl]guanidineor or a pharmaceutically acceptable salt thereof.

The preferred and especially preferred NHE-1 inhibitors disclosed in theabove two paragraphs can be prepared according to methods set forth inInternational Patent Application No. PCT/IB99/00206 or as set forthbelow, where the variables in the following schemes and descriptionrefer only to the NHE-1 compounds.

According to Scheme I, the Formula I-a compound, wherein R⁴ is asdescribed above for the compound of formula NHE, is dissolved orsuspended in an aqueous alkali metal hydroxide solution (e.g. 1 N sodiumhydroxide) along with sodium nitrite and the mixture is added to anaqueous acidic solution (e.g. 10% v/v sulfuric acid) at a pH of about 0at a temperature of about 0° C. to about 5° C. for about 30 min to about1 hour. The resulting mixture is filtered to yield the Formula I-boxime. Alternatively, the Formula I-a compound is dissolved in 1:1acetic acid/propionic acid and solid sodium nitrite is added at about 0°C. The reaction mixture is stirred at about 0° C. for about 2 hours,then poured into ice water and the Formula I-b oxime is obtained byfiltration.

The Formula I-b compound is reacted with a Formula I-c compound, whereinR⁵ is as described above for the compound of formula NHE in a proticsolvent such as ethanol at a temperature of about 50° C. to about 110°C. for about 10 min to about 1 hour to form the Formula I-d hydrazone.

The Formula I-d hydrazone is cyclized and hydrolyzed to the Formula Itriazole in an alcoholic solvent such as 2-ethoxyethanol under basicconditions (e.g. potassium hydroxide) at a temperature of about 100° C.to about 175° C. for about {fraction (1/2)} hour to about 2 hoursfollowed by acidification to yield the Formula I-e triazole acid.

The Formula I-e acid is coupled with guanidine in the presence of asuitable coupling agent. A suitable coupling agent is one whichtransforms a carboxylic acid into a reactive species which forms anamide linkage on reaction with an amine.

The coupling agent may be a reagent which effects this condensation in aone pot process when mixed together with the carboxylic acid andguanidine. Exemplary coupling reagents are1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride-hydroxybenzotriazole (EDC/HBT),dicyclohexylcarbodiimide/hydroxybenzotriazole (HBT),2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), anddiethylphosphorylcyanide. The coupling is performed in an inert solvent,preferably an aprotic solvent at a temperature of about −20° C. to about50° C. for about 1 to about 48 hours, in the presence of excessguanidine as base. Exemplary solvents include acetonitrile,dichloromethane, dimethylformamide and chloroform or mixtures thereof.

The coupling agent may also be that agent which converts the carboxylicacid to an activated intermediate which is isolated and/or formed in afirst step and allowed to react with guanidine in a second step.Examples of such coupling agents and activated intermediates are thionylchloride or oxalyl chloride to form the acid chloride, cyanuric fluorideto form an acid fluoride or an alkyl chloroformate such as isobutyl orisopropenyl chloroformate or propanephosphonic anhydride(propanephosphonic acid anhydride, PPA) (with a tertiary amine base) toform a mixed anhydride of the carboxylic acid, or carbonyldiimidazole toform an acylimidazole. If the coupling agent is oxalyl chloride, it isadvantageous to employ a small amount of dimethylformamide as cosolventwith another solvent (such as dichloromethane) to catalyze the formationof the acid chloride. This activated acid derivative may be coupled bymixing with excess guanidine in an appropriate solvent together with anappropriate base. Appropriate solvent/base combinations are for example,dichloromethane, dimethylformamide or acetonitrile or mixtures thereofin the presence of excess guanidine as base. Other appropriatesolvent/base combinations include water or a (C₁-C₅)alcohol or a mixturethereof together with a cosolvent such as dichloronmethane,tetrahydrofuran or dioxane and a base such as sodium, potassium orlithium hydroxide in sufficient quantity to consume the acid liberatedin the reaction. Use of these coupling agents and appropriate selectionof solvents and temperatures are known to those skilled in the art orcan be readily determined from the literature. These and other exemplaryconditions useful for coupling carboxylic acids are described inHouben-Weyl, Vol XV, part 11, E. Wunsch, Ed., G. Theime Verlag, 1974,Stuttgart; M. Bodansky, Principles of Peptide Synthesis,Springer-Verlag, Berlin 1984; and The Peptides, Analysis, Synthesis andBiology (ed. E. Gross and J. Meienhofer), vols 1-5 (Academic Press, NY1979-1983).

According to Scheme II, the Formula II-a primary amine wherein R⁵ is asdescribed above for the compound of formula NHE is reacted with aFormula II-b α-diazo-β-keto-ester wherein R⁴ is as described above forthe compound of formula NHE, and R is lower alkyl, in the presence oftitanium tetrachloride analogously to the method described in Eguchi S.et al. Synthesis 1993, 793 to form the Formula II-c triazole carboxylicacid ester. The Formula II-c ester is converted directly to theacylguanidine II-d by reaction with guanidine in an alcoholic solvent ata temperature of about 60 to about 110° C., preferably refluxingmethanol, for a period of 8 to 20 hours.

According to Scheme III, the Formula II-a compound wherein R⁴ and R⁵ areas described above for the compound of formula NHE is treated withLawesson's reagent (i.e.,2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide) inan aprotic solvent such as dimethoxyethane at a temperature of about 20°C. to about 120° C. for about one to eight hours. The resultingthioamide is treated with an alkylating agent such as methyl iodide in apolar, inert solvent such as acetone, conveniently at ambienttemperature for about eight hours to about forty-eight hours. Theresulting compound is reacted with anhydrous hydrazine in an alcoholicsolvent at a temperature of about 0° C. to about 25° C. for about one toeight hours to provide the Formula III-b compound (analogously asdescribed in Doyle and Kurzer, Synthesis 1974, 583).

The Formula III-b compound is treated with a monoalkyloxalyl chloride inan aprotic solvent at a temperature of about 25° C. to about 50° C. forabout one to eight hours to provide the Formula II-c carboxylic estercompound wherein R is lower alkyl. The Formula III-c ester is directlycoupled with guanidine in an alcoholic solvent at a temperature of about60° C. to about 110° C., preferably refluxing methanol, for a period ofeight to twenty hours, to prepare the Formula II-d triazole carbonylguanidines.

According to Scheme IV the Formula IV-a compound wherein R⁵ is as,described above for the compound of formula NHE is treated with methyliodide in an inert solvent, conveniently at ambient temperature forabout four to twenty-four hours. The resulting compound is reacted withanhydrous R⁴-hydrazine (wherein R⁴ is as described above for thecompound of formula NHE) in an alcoholic solvent at a temperature ofabout 0° C. to about 25° C. for about one to eight hours to provide the,Formula IV-b amidrazone compound (analogously as described in Doyle andKurzer, Synthesis 1974, 583).

The Formula IV-b compound is treated with a monoalkyloxalyl chloride inan aprotic solvent at a temperature of about 25° C. to about 50° C. forabout one to eight hours to provide the Formula IV-c carboxylic estercompound wherein R is lower alkyl. The Formula IV-c ester is directlycoupled with guanidine in an alcoholic solvent at a temperature of about60° C. to about 110° C., preferably refluxing methanol, for a period ofeight to twenty hours to prepare the Formula IV-d triazole carbonylguanidines.

According to Scheme V the Formula V-a compound wherein R¹ is asdescribed above for the compound of formula NHE is combined with excess(CH₃O)₂C(R³)N(CH₃)₂ (N,N-dimethyl amide dimethyl acetal) wherein R³ isas described above for the compound of formula NHE, optionally in thepresence of an acid catalyst such as ptoluenesulfonic acid at atemperature of about 90° C. to about 110° C. for about one to about twohours to prepare the Formula V-c compound above.

The Formula V-c compound is cyclized with a Formula V-d compound,wherein R² is as described above for the compound of formula NHE, in aninert solvent such as ethanol at a temperature of about 20° C. to about30° C. for about 5 minutes to about one hour followed by heating to atemperature of about 70° C. to about 110° C. for about two hours toabout four hours to form the Formula V-f pyrazole.

Alternatively, according to Scheme V the Formula V-a compound, whereinR¹ is as described above for the compound of formula NHE, is combinedwith a triethylorthoester (i.e., R³C(OEt)₃ wherein R³ is as describedabove for the compound of formula NHE), and acetic anhydride at atemperature of about 120° C. to about 150° C. for about two to aboutfive hours to prepare the Formula V-b compound.

The Formula V-b compound is cyclized with a Formula V-d compound,wherein R² is as described above for the compound of formula NHE, toform the Formula V-c pyrazole.

The Formula V-c pyrazole is hydrolyzed with a base such as sodiumhydroxide or lithium hydroxide in a solvent such as water and/ormethanol and/or THF conveniently at ambient temperature or at elevatedtemperature (e.g., reflux) for about one hour to about five hours toprepare the Formula V-f acid.

The Formula V-f acid is coupled with guanidine in the presence of asuitable coupling agent as described for the above coupling of theFormula I-e acid and guanidine. In one embodiment, the Formula V-f acidis activated with thionyl chloride at a temperature of about 60° C. toabout 90° C. for about fifteen minutes to about two hours. The resultingactivated acid chloride is combined with guanidine hydrochloride and aninorganic base (e.g., sodium hydroxide) in anhydrous tetrahydrofuran andoptionally methanol and/or water. The solution is heated, convenientlyat reflux, for about one hour to about eight hours to prepare theFormula V-g compound.

Alternatively according to Scheme V the Formula V-e compound can bedirectly converted to the Formula V-g compound by several methods. Forexample, the Formula V-e compound can be heated in the presence ofexcess guanidine, in a polar protic solvent for example, methanol orisopropanol at a suitable temperature conveniently, at reflux for aboutone to about seventy-two hours. This transformation may also beperformed by repeatedly removing the solvent, for example removingethanol or toluene about four times, from a mixture of the Formula V-ecompound and excess guanidine at a pressure of about one to about 100mmHg and at a temperature of about 25° C. to about 95° C. This reactionmay also be performed in the absence of solvent by heating the mixtureof the Formula V-e compound and excess guanidine at a temperature ofabout 100° C. to about 180° C., optionally at about a pressure of about1 to about 100 mmHg for about five minutes to about eight hours.

According to Scheme VI, the Formula VI-a compound, wherein R³ is asdescribed above for the compound of formula NHE, is reacted with theFormula VI-b compound, wherein R¹ and R² are as described above for thecompound of formula NHE, in an aprotic solvent at a temperature of about0° C. to about 25° C. for about two hours to about twenty-four hours inthe presence of an appropriate amine base, such as triethylamine, toform the Formula VI-c compound.

The resulting Formula VI-c compound is hydrolyzed and coupled withguanidine using one of the methods described in earlier Schemes, such asthe method employing carbonyldiimidazole, to form the Formula VI-dcompound.

According to Scheme VII, the Formula VII-a hydrazine, wherein R² is asdescribed above for the compound of formula NHE, is reacted with theappropriate Formula VII-b compound to form the Formula VII-c pyrazoleester wherein R is lower alkyl according to the method of Bajnati, A.and Hubert-Habart, M. Bull. Soc. Chim. France 1988, 540. The resultingpyrazole ester is converted to the Formula VII-d acyl guanidine usingthe hydrolysis and coupling methods described above.

According to Scheme VIII, the Formula VIII-a compound wherein R² and R¹are as described above for the compound of formula NHE is transformed tothe Formula VII-b lithium salt where R³ is lower alkyl according to themethod described in J. Het. Chem. 1989, 26, 1389. The Formula VIII-blithium salt is combined with the Formula VIII-c hydrazine, wherein R³is as described above for the compound of formula NHE, in an inertsolvent such as ethanol, in the presence of a mineral acid, at atemperature of about 20° C. to about 30° C. for about five minutes toabout one hour followed by heating to a temperature of about 70° C. toabout 110° C. for two hours to about four hours to form both the FormulaVIII-d and VII-e pyrazoles. The Formula VIII-d and VIII-e pyrazoles areconverted to the Formula VIII-f and VIII-g acyl guanidines respectivelyusing the hydrolysis and coupling methods described above. Some of themethods useful for the preparation of the compounds described herein mayrequire protection of remote functionality (e.g., primary amine,secondary amine, carboxyl in Formula I precursors). The need for suchprotection will vary depending on the nature of the remote functionalityand the conditions of the preparation methods. The need for suchprotection is readily determined by one skilled in the art. The use ofsuch protection/deprotection methods is also within the skill in theart. For a general description of protecting groups and their use, seeT. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons,New York, 1991.

The compounds of formula I of the present invention, when used incombination with NHE-1, inhibitors, inhibit the sodium/proton (Na⁺/H⁺)exchange transport system and hence are useful as a therapeutic orprophylactic agent for diseases caused or aggravated by the accelerationof the sodium/proton (Na⁺/H⁺) exchange transport system, for example,cardiovascular diseases [e.g., arteriosclerosis, hypertension,arrhythmia (e.g. ischemic arrhythmia, arrhythmia due to myocardialinfarction, myocardial stunning, myocardial dysfunction, arrhythmiaafter PTCA or after thrombolysis, etc.), angina pectoris, cardiachypertrophy, myocardial, infarction, heart failure (e.g. congestiveheart failure, acute heart failure, cardiac hypertrophy, etc.),restenosis after PTCA, PTCI, shock (e.g. hemorrhagic shock, endotoxinshock, etc.)], renal diseases (e.g. diabetes mellitus, diabeticnephropathy, ischemic acute renal failure, etc.) organ disordersassociated with ischemia or ischemic reperfusion [e.g. heart muscleischemic reperfusion associated disorders, acute renal failure, ordisorders induced by surgical treatment such as coronary artery bypassgrafting (CABG) surgeries, vascular surgeries, organ transplantation,non-cardiac surgeries or percutaneous transluminal coronary angioplasty(PTCA)], cerebrovascular diseases (e.g. ischemic stroke, hemorrhagicstroke, etc.), cerebro ischemic disorders (e.g. disorders associatedwith cerebral infarction, disorders caused after cerebral apoplexy assequelae, or cerebral edema.

Preferably, the compounds of formula I of this invention can be used incombination with NHE-1 inhibitors as agents for myocardial protectionbefore, during, or after coronary artery bypass grafting (CABG)surgeries, vascular surgeries, percutaneous transluminal coronaryangioplasty (PTCA), organ transplantation, or non-cardiac surgeries.

Preferably, the compounds of formula I of this invention can be used incombination with NHE-1 inhibitors as agents for myocardial protection inpatients presenting with ongoing cardiac (acute coronary syndromes, e.g.myocardial infarction or unstable angina) or cerebral ischemic events(e.g. stroke).

Preferably, the compounds of formula I of this invention can be used incombination with NHE-1 inhibitors as agents for chronic myocardialprotection in patients with diagnosed coronary heart disease (e.g.previous myocardial infarction or unstable angina) or patients who areat high risk for myocardial infarction (age greater than 65 and two ormore risk factors for coronary heart disease).

In addition, a combination of the compounds of formula I of thisinvention with NHE-1 inhibitors has a strong inhibitory effect on theproliferation of cells, for example the proliferation of fibroblastcells and the proliferation of the smooth muscle cells of the bloodvessels. For this reason, the combination of the compounds of formula Iof this invention with NHE-1 inhibitors of this invention is a valuabletherapeutic agent for use in diseases in which cell proliferationrepresents a primary or secondary cause and may, therefore, be used asantiatherosclerotic agents, and as agents against diabetic latecomplications, cancerous diseases, fibrotic diseases such as pulmonaryfibrosis, hepatic fibrosis or renal fibrosis, glomerularnephrosclerosis, organ, hypertrophies or hyperplasias, in particularhyperplasia or hypertrophy of the prostate, pulmonary fibrosis, diabeticcomplications or recurrent stricture after PTCA, or diseases caused byendothelial cell injury.

The utility of the combination of compounds of the present inventionwith NHE-1 inhibitors as medical agents in the treatment of diseases,such as are detailed herein in mammals (e.g. humans) for example,myocardial protection during surgery, or mycardial protection inpatients presenting with ongoing cardiac or cerebral ischemic events orchronic cardioprotection in patients with diagnosed coronary heartdisease, or at risk for coronary heart disease, cardiac, dysfunction ormyocardial, stunning is demonstrated by the activity of said combinationin conventional preclinical cardioprotection assays [see the in vivoassay in Klein, H. et al., Circulation 92:912-917 (1995); the isolatedheart assay in Scholz, W. et al., Cardiovascular Research 29:260-268(1995); the antiarrhythmic assay in Yasutake M. et al., Am. J. Physiol.,36:H2430-H2440 (1994); the NMR assay in Kolke et al., J. Thorac.Cardiovasc. Surg. 112: 765-775 (1996)] and the additional in vitro andin vivo assays described below. Such assays also provide a means wherebythe activities of the compounds of formula I of this invention can becompared with the activities of other known compounds. The results ofthese comparisons are useful for determining dosage levels in mammals,including humans, for the treatment of such diseases.

Measurement of Human NHE-1 Inhibitory Activity

Methodologies for measurement of human NHE-1 activity and inhibitorpotency are based on those published by Watson et al., Am. J. Physiol.,24:G229-G238, 1991), where NHE-mediated recovery of intracellular pH ismeasured following intracellular acidification. Thus, fibroblasts stablyexpressing human NHE-1 (Counillon, L. et al., Mol. Pharmacol.,44:1041-1045 (1993) are plated onto collagen coated 96 well plates(50,000/well) and grown to confluence in growth media (DMEM highglucose, 10% fetalibovine serum, 50 u/ml penicillin and streptomycin).Confluent plates are incubated for 30 minutes at 37° C. with the pHsensitive fluorescent probe BCECF (5 μM; Molecular Probes, Eugene,Oreg.). BCECF loaded cells are incubated for 30 minutes at 37° C. inacid loading media (70 mM choline chloride, 50 mM NHCl₄, 5 mM KCl, 1 mMMgCl₂, 1.8 mM CaCl₂, 5 mM glucose, 10 mM HEPES, pH 7.5), and then placedin a Fluorescent Imaging Plate Reader (Molecular Devices, CA). BCECFfluorescence is monitored using excitation and emission wavelengths of485 nM and 525 nM, respectively. Intracellular acidification isinitiated via rapid replacement of acid loading media with recoverymedia (120 mM NaCl, 5 mM KCl, 1 mM MgCl₂, 1.8 mM CaCl₂, 5 mM glucose, 10mM HEPES, pH 7.5)±test combination, and NHE-mediated recovery ofintracellular pH is monitored as the subsequent time-dependent increaseBCECF fluorescence. The potency of the combinations of the compounds offormula I of this invention with NHE-1 inhibitors is calculated as theconcentration that reduces recovery of intracellular pH by 50% (IC₅₀).Under these conditions reference NHE inhibitors amiloride and HOE-642had IC₅₀ values for human NHE-1 of 50 μM and 0.5 μM, respectively.

As background information, it is noted that brief periods of myocardialischemia followed by coronary artery reperfusion protects the heart fromsubsequent severe myocardial ischemia (Murry et al., Circulation74:1124-1136, 1986).

The therapeutic effects of the combination of the compounds of formula Iof this invention with NHE-1 inhibitors in preventing heart tissuedamage resulting from an ischemic insult can be demonstrated in vitroalong lines presented in Liu et al. (Cardiovasc. Res., 28:1057-1061,1994), as described specifically herein. Cardioprotection, as indicatedby a reduction in infarcted myocardium, can be induced pharmacologicallyusing adenosine receptor agonists in isolated, retrogradely perfusedrabbit hearts as an in vitro model of myocardial ischemicpreconditioning (Liu et al., Cardiovasc. Res., 28:1057-1061, 1994). Thein vitro test described below demonstrates that a test compound or, inthis case a test combination (i.e., a combination of a compound offormula I with an NHE-1 antagonist) can also pharmacologically inducecardioprotection, i.e., reduced myocardial infarct size, whenadministered to a rabbit isolated heart. The effects of the testcombination are compared to ischemic preconditioning and the A1/A3adenosine agonist, APNEA (N⁶-[2-(4-aminophenyl)ethyl]adenosine), thathas been shown to pharmacologically induce cardioprotection in therabbit isolated heart (Liu et al., Cardiovasc. Res., 28:1057-1061,1994).The exact methodology is described below.

The protocol used for these experiments closely follows that describedby Liu et al., Cardiovasc. Res., 28:1057-1061,1994. Male New ZealandWhite rabbits (34 kg) are anesthetized with sodium pentobarbital (30mg/kg, i.v.). After deep anesthesia is achieved (determined by theabsence of an ocular blink reflex) the animal is intubated andventilated with 100% O₂ using a positive pressure ventilator. A leftthoracotomy is performed, the heart exposed, and a snare (2-0 silk) isplaced loosely around a prominent branch of the left coronary artery,approximately {fraction (2/3)} of the distance towards the apex of theheart. The heart is removed from the chest and rapidly (<30 sec) mountedon a Langendorff apparatus. The heart is retrogradely perfused in anon-recirculating manner with a modified Krebs solution (NaCl 118.5 mM,KCl 4.7 mM, Mg SO₄ 1.2 mM, KH₂PO₄ 1.2 mM, NaHCO₃ 24.8 mM, CaCl₂ 2.5 mM,and glucose 10 mM), at a constant pressure of 80 mmHg and a temperatureof 37° C. Perfusate pH is maintained at 7.4-7.5 by bubbling with 95%O₂/5% CO₂. Heart temperature is tightly controlled by using heatedreservoirs for the physiological solution and water jacketing aroundboth the perfusion tubing and the isolated heart. Heart rate and leftventricular pressures are determined via a latex balloon which isinserted in the left ventricle and connected by stainless steel tubingto a pressure transducer. The intraventricular balloon is inflated toprovide a systolic pressure of 80-100 mmHg, and a diastolic pressure≦10mmHg. Total coronary flow is also continuously monitored using anin-line flow probe and normalized for heart weight.

The heart is allowed to equilibrate for 30 minutes, over which time theheart must show stable left ventricular pressures within the parametersoutlined above. If the heart rate falls below 180 bpm at any time priorto the 30 minutes period of regional ischemia, the heart is paced atabout 200 bpm for the remainder of the experiment. Ischemicpreconditioning is induced by total cessation of cardiac perfusion(global ischemia) for 5 minutes, followed by reperfusion for 10 minutes.The regional ischemia is provided by tightening the snare around thecoronary artery branch. Following the 30 minutes regional ischemia, thesnare is released and the heart reperfused for an additional 120minutes.

Pharmacological cardioprotection is induced by infusing the testcombination, i.e., a combination of a compound of formula I with anNHE-1 inhibitor, at predetermined concentrations, starting 30 minutesprior to the 30 minutes regional ischemia, and continuing until the endof the 120 minutes reperfusion period. Hearts which receive, the testcombination do not undergo the period of ischemic preconditioning. Thereference compound, APNEA (500 nM) is perfused through hearts (which donot receive the test compound) for a 5 minutes period which ends 10minutes before the 30 minutes regional ischemia.

At the end of the 120 minutes reperfusion period, the coronary arterysnare is tightened, and a 0.5% suspension of fluorescent zinc cadmiumsulfate particles (1-10 μM) Duke Scientific Corp. (Palo Alto, Calif.) isperfused through the heart; this stains all of the myocardium, exceptthat area-at-risk for infarct development (area-at-risk). The heart isremoved from the Langendorff apparatus, blotted dry, wrapped in aluminumfoil and stored overnight at −20° C. The next day, the heart is slicedinto 2 mm transverse sections from the apex to the top of theventricles. The slices are stained with 1% triphenyl tetrazoliumchloride (TTC) in phosphate-buffered saline for 20 minutes at 37° C.Since TTC reacts with living tissue (containing NAD-dependentdehydrogenases), this stain differentiates between living (red stained)tissue, and dead tissue (unstained infarcted tissue). The infarcted area(no stain) and the area-at-risk (no fluorescent particles) arecalculated for each slice of left ventricle using a precalibrated imageanalyzer. To normalize the ischemic injury for differences in thearea-at-risk between hearts, the data is expressed as the ratio ofinfarct area vs. area-at-risk (% IA/AAR). All data are expressed asmean±SE and compared statistically using a Mann-Whitney non-parametrictest with a Bonferroni correction for multiple comparisons. Significanceis considered as p<0.05.

The results from the above in vitro test demonstrate that a combinationof a compound of this invention with an NHE-1 inhibitor inducesignificant cardioprotection relative to the control group.

The therapeutic effects of a combination of a compound of formula I ofthis invention with an NHE-1 inhibitor in preventing heart tissue damageotherwise resulting from an ischemic insult can also be demonstrated invivo along lines presented in Liu et al. (Circulation, Vol. 84:350-356,1991) as described specifically herein. The in vivo assay tests thecardioprotection of the test combination, i.e., a compound of formula Itogether with an NHE-1 inhibitor, relative to the control group whichreceives saline vehicle. Cardioprotection, as indicated by a reductionin infarcted myocardium, can be induced pharmacologically usingintravenously administered adenosine receptor agonists in intact,anesthetized rabbits studied as an in situ model of myocardial ischemicpreconditioning (Liu et al., Circulation 84:350-356, 1991). The in vivoassay tests whether the instant combination of a compound of formula Iwith an NHE-1 inhibitor can pharmacologically induce cardioprotection,i.e., reduced myocardial infarct size, when parenterally administered tointact, anesthetized rabbits. The effects of the combination of acompound of formula I of this invention with an NHE-11 inhibitor can becompared to ischemic preconditioning using the A1 adenosine agonist,N⁶-1-(phenyl-2R-isopropyl) adenosine (PIA) that has been shown topharmacologically induce cardioprotection in intact anesthetized rabbitsstudied in situ (Liu et al., Circulation 84:350-356, 1991). Themethodology is described below.

Surgery: New Zealand White male rabbits (34 kg) are anesthetized withsodium pentobarbital (30 mg/kg, i.v.). A tracheotomy is performed via aventral midline cervical incision and the rabbits are ventilated with100% oxygen using a positive pressure ventilator. Catheters are placedin the left jugular vein for drug administration and in the left carotidartery for blood pressure measurements. The hearts are then exposedthrough a left thoracotomy and a snare (00 silk) placed around aprominent branch of the left coronary artery., Ischemia is induced, bypulling the snare tight and clamping it in place. Releasing the snareallows the affected area to reperfuse. Myocardial ischemia is evidencedby regional cyanosis; reperfusion is evidenced by reactive hyperemia.

Protocol: Once arterial pressure and heart rate have been stable for atleast 30 minutes the test is started. Ischemic preconditioning isinduced by occluding the coronary artery for 5 minutes followed by a 10minutes reperfusion. Pharmacological preconditioning is induced byinfusing the test combination, i.e., a combination of a compound offormula I of this invention with an NHE-1 inhibitor, over, for example,5 minutes and allowing 10 minutes before further intervention or byinfusing the adenosine agonist, PIA (0.25 mg/kg). Following ischemicpreconditioning, pharmacological preconditioning or no conditioning(unconditioned, vehicle control) the artery is occluded for 30 minutesand then reperfused for two hours to induce myocardial infarction. Thetest combination and PIA are dissolved in saline or other suitablevehicle and delivered at 1 to 5 mg/kg, respectively.

Staining (Liu et al., Circulation 84:350-356, 1991): At the end of the 2hour reperfusion period, the hearts are quickly removed, hung on aLangendorff apparatus, and flushed for 1 minute with normal salineheated to body temperature (38° C.). The silk suture used as the snareis then tied tightly to reocclude the artery and a 0.5% suspension offluorescent zinc cadmium sulphate particles (1-10 μm) Duke ScientificCorp. (Palo Alto, Calif.) is infused with the perfusate to stain all ofthe myocardium except the area at risk (nonfluorescent ventricle). Thehearts are then quickly frozen and stored overnight at −20° C. On thefollowing day, the hearts are cut into 2 mm slices and stained with 1%triphenyl tetrazolium chloride (TTC). Since TTC reacts with livingtissue, this stain differentiates between living (red stained) tissue,and dead tissue (unstained infarcted tissue). The infarcted area (nostain) and the area at risk (no fluorescent particles) are calculatedfor each slice of left ventricle using a pre-calibrated image analyzer.To normalize the ischemic injury for differences in the area at riskbetween hearts, the data is expressed as the ratio of infarct area vs.area at risk. (% IA/AAR). All data are expressed as Mean±SEM andcompared statistically using single factor ANOVA or Mann Whitney nonparametric test. Significance is considered as p<0.05.

The combination of a compound of formula I of this invention with anNHE-1 inhibitor can be tested for their utility in reducing orpreventing ischemic injury in non-cardiac tissues, for example, thebrain, or the liver, utilizing procedures reported in the scientificliterature. The combination of a compound of formula I of this inventionwith an NHE-1 inhibitor in such tests can be administered by thepreferred route and vehicle of administration and at the preferred timeof administration either prior to the ischemic episode, during theischemic episode, following the ischemic episode (reperfusion period) orduring any of the below-mentioned experimental stages.

The benefit of the combination of NHE-1 inhibitors and compounds offormula 1 of this invention to reduce ischemic brain damage can bedemonstrated, for example, in mammals using the method of Park, et al(Ann. Neurol. 1988;24:543-551). According to the procedure of Park, etal., adult male Sprague Dawley rats are anesthetized initially with 2%halothane, and thereafter by mechanical ventilation with a nitrousoxide-oxygen mixture (70%:30%) containing 0.5-1% halothane. Atracheostomy is then performed. The stroke volume of the ventilator isadjusted to maintain arterial carbon dioxide tension at approximately 35mmHg and adequate arterial oxygenation (PaO₂>90 mmHg). Body temperaturecan be monitored by a rectal thermometer, and the animals can bemaintained normothermic, if necessary, by external heating. The animalsnext undergo subtemporal craniectomy to expose the main trunk of theleft middle cerebral artery (MCA) under an operating microscope, and theexposed artery is occluded with, microbipolar coagulation to generatelarge ischemic lesions in the cerebral cortex and basal ganglia. Afterthree hours of MCA occlusion, the rats are deeply anesthetized with 2%halothane and a thoracotomy is performed to infuse heparinized salineinto the left ventricle. The effluent is collected via an incision ofthe right atrium. The saline washout is followed by approximately 200 mlof a 40% formaldehyde, glacial acetic acid and absolute methanolsolution (FAM; 1:1:8, v/v/v), then the animals are decapitated and thehead is stored in fixative for 24 hours. The brain is then removed,dissected, embedded in paraffin wax, and sectioned (approximately 100sections 0.2 mm per brain). The sections are then stained withhematoxylin-eosin or with a combination of cresyl violet and Luxol fastblue, and examined by light microscopy to identify and quantitate theischemic damage using a precalibrated image analyzer. The ischemicvolumes and areas are expressed in absolute units (mm³ and mm²) and as apercentage of the total region examined. The effect of the compositionsand methods of this invention to reduce ischemic brain damage induced byMCA occlusion is noted based on a reduction in the area or volume ofrelative or absolute ischemic damage in the brain sections from the ratsin the treatment group compared to brain sections from rats in aplacebo-treated control group.

Other methods which could alternatively be utilized to demonstrate thebenefit of the invention to reduce ischemic brain damage include thosedescribed by Nakayama, et al. in Neurology 1988, 38:1667-1673; Memezawa,et al. in Stroke 1992, 23:552-559; Folbergrova, et al. in Proc. Natl.Acad. Sci 1995, 92:5057-5059; and Gotti, et al. in Brain Res. 1990,522:290-307.

The benefit of the compositions and methods of this invention to reduceischemic liver damage can be demonstrated, for example, in mammals usingthe method of Yokoyama, et al. (Am. J. Physiol. 1990;258:G564-G570).According to the procedure of Yokoyama, et al., fasted adult maleSprague Dawley rats are anesthetized with sodium pentobarbital (40 mg/kgi.p.), then the animals are tracheotomized and mechanically ventilatedwith room air. The liver is extirpated and placed in an environmentalchamber maintained at constant temperature (37° C.), then perfusedthrough the portal vein at a constant pressure of 15 cm H₂O with amodified, hemoglobin-free Krebs-Henseleit buffer (in mM: 118 NaCl, 4.7KCl, 27 NaHCO₃, 2.5 CaCl₂, 1.2 MgSO₄, 1.2 KH₂PO₄, 0.05 EDTA, and 11 mMglucose, plus 300 U heparin). The pH of the perfusate is maintained at7.4 by gassing the buffer with 95% O₂-5% CO₂. Each liver is perfused ata flow rate of 20 ml/minutes in a single-pass manner for a 30 minuteswashout and equilibration period (preischemic period), followed by a 2hour period of global ischemia, and then a 2 hour period of reperfusionunder conditions identical to the preischemic period. Aliquots (20 ml)of the perfusate are collected during the preischemic period,immediately after the occlusive ischemic period, and every 30 minutes ofthe 2 hour reperfusion period. The perfusate samples are assayed for theappearance of hepatocellular enzymes, for example, aspartateamino-transferase (AST), alanine amino-transferase (ALT), and lactatedehydrogenase (LDH), which are taken to quantitatively reflect thedegree of ischemic liver tissue damage during the procedure. AST, ALT,and LDH activities in the perfusate can be determined by severalmethods, for example, by the reflectometry method using an automaticKodak Ektachem 500 analyzer reported by Nakano, et al. (Hepatology1995;22:539-545). The effect of the compositions and methods of thisinvention in reducing ischemic liver damage induced by occlusion isnoted based on a reduction in the release of hepatocellular enzymesimmediately following the occlusive period and/or during thepostischemic-reperfusion period in the perfused livers from the rats inthe treatment group compared to perfused livers from rats in aplacebo-treated control group.

Other methods and parameters which could alternatively be utilized todemonstrate the benefit of the compositions and methods of thisinvention in reducing ischemic liver damage include those described byNakano, et al. (Hepatology 1995;22:539-545).

Any glycogen phosphorylase inhibitor may be used as the second compoundof this invention. The term glycogen phosphorylase inhibitor refers toany substance or agent or any combination of substances and/or agentswhich reduces, retards, or eliminates the enzymatic action of glycogenphosphorylase. The currently known enzymatic action of glycogenphosphorylase is the degradation of glycogen by catalysis of thereversible reaction of a glycogen macromolecule and inorganic phosphateto glucose-1-phosphate and a glycogen macromolecule which is oneglucosyl residue shorter than the original glycogen macromolecule(forward direction of glycogenolysis). Such actions are readilydetermined by those skilled in the art according to standard assays(e.g., as described hereinafter). A variety of these compounds areincluded in the following published PCT patent applications: PCTapplication publication WO 96/39384 and WO96/39385. However, otherglycogen phosphorylase inhibitors will be known to those skilled in theart.

Compounds of formula I, prodrugs thereof, mutual prodrugs of thecompounds of formula I with aldose reductase inhibitors,pharmaceutically acceptable salts of any of the above and pharmaceuticalcompositions comprising a compound of formula I, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug andeither (a) an aldose reductase inhibitor, a prodrug thereof or apharmaceutically acceptable salt of said aldose reductase inhibitor orsaid prodrug, (b) a NHE-1 inhibitor, a prod rug thereof or apharmaceutically acceptable salt of said NHE-1 inhibitor or saidprodrug, or a glycogen phosphorylase inhibitor, a prodrug thereof or apharmaceutically acceptable salt of said glycogen phosphorylaseinhibitor or said prodrug are hereinafter referred to, collectively, as“the active compounds and compositions of this invention.”

The active compounds and compositions of this invention may beadministered to a subject in need of treatment by a variety ofconventional routes of administration, including orally, parenterallyand topically. In general, compounds of the formula I and theirpharmaceutically acceptable salts will be administered orally orparenterally at dosages between about 0.001 and about 100 mg/kg bodyweight of the subject to be treated per day, preferably from about 0.01to 10 mg/kg, in single or divided doses. Mutual prodrugs of compounds ofthe formula I and aldose reductase inhibitors will generally beadministered orally or parenterally at dosages between about 0.001 andabout 100 mg/kg body weight of the subject to be treated per day,preferably from about 0.01 to about 10 mg/kg, in single or divideddoses. Compositions containing both a compound of the formula I and analdose reductase inhibitor will generally be administered orally orparenterally at dosages between about 0.001 and about 100 mg of eachactive component (i.e., the compound of formula I and the aldosereductase inhibitor) per kg body weight of the subject to be treated perday, preferably from about 0.01 to about 10 mg/kg. Compositionscontaining both a compound of formula I and a NHE-1 inhibitor willgenerally be administered orally or parenterally at dosages betweenabout 0.001 and 100 mg of said compound of formula I per kg body weightof the subject to be treated per day and about 0.001 to 100 mg/kg/day ofthe NHE-1 inhibitor. An especially preferred dosage contains betweenabout 0.01 and 10 mg/kg/day of said compound of formula I and betweenabout 0.01 and 50 mg/kg/day of said NHE-1 inhibitor. Compositionscontaining both a compound of formula I and a glcogen phosphorylaseinhibitor will generally be administered orally or parenterally atdosages between about 0.001 and 100 mg of said compound of formula I perkg body weight of the subject to be treated per day and 0.005 to 50mg/kg/day of said glycogen phosphorylase inhibitor, preferably 0.01 and10 mg/kg/day of said compound of formula and 0.01 to 25 mg/kg/day ofsaid glycogen phosphorylase inhibitor and most preferably 0.01 and 10mg/kg/day of said compound of formula and 0.1 to 15 mg/kg/day of saidglycogen phosphorylase inhibitor. However, some variation in dosage willnecessarily occur depending on the condition of the subject beingtreated. The person responsible for administration will, in any event,determine the appropriate dose for the individual subject.

The active compounds and compositions of this invention, may beadministered alone or in combination with pharmaceutically acceptablecarriers, in either single or multiple doses. Suitable pharmaceuticalcarriers include inert solid diluents or fillers, sterile aqueoussolutions and various organic solvents. The pharmaceutical compositionsformed by combining the active compounds of formula I of this inventionand the pharmaceutically acceptable carriers are then readilyadministered in a variety of dosage forms such as tablets, powders,lozenges, syrups, injectable solutions and the like. Thesepharmaceutical compositions can, if desired, contain additionalingredients such as flavorings, binders, excipients and the like. Thus,for purposes of oral administration, tablets containing variousexcipients such as sodium citrate, calcium carbonate and calciumphosphate may be employed along with various disintegrants such asstarch, alginic acid and certain complex silicates, together withbinding agents such as polyvinylpyrrolidone, sucrose, gelatin andacacia. Additionally, lubricating agents such as magnesium stearate,sodium lauryl sulfate and talc are often useful for tabletting purposes.Solid compositions of a similar type may also be employed as fillers insoft and hard filled gelatin capsules. Preferred materials for thisinclude lactose or milk sugar and high molecular weight polyethyleneglycols. When aqueous suspensions or elixirs are desired for oraladministration, the essential active ingredient therein may be combinedwith various sweetening or flavoring agents, coloring matter or dyesand, if desired, emulsifying or suspending agents, together withdiluents such as water, ethanol, propylene glycol, glycerin andcombinations thereof.

For parenteral administration, solutions of the active compounds andcompositions of this invention in sesame or peanut oil, aqueouspropylene glycol, or in sterile aqueous solutions may be employed. Suchaqueous solutions should be suitably buffered if necessary and theliquid diluent first rendered isotonic with sufficient saline orglucose. These particular aqueous solutions are especially suitable forintravenous, intramuscular, subcutaneous and intraperitonealadministrator. In this connection, the sterile aqueous media employedare all readily available by standard techniques known to those skilledin the art.

Administration of the compounds of formula I of this invention can bevia any method which delivers a compound of this inventionpreferentially to the desired tissue (e.g., nerve, kidney, retina and/orcardiac tissues). These methods include oral routes, parenteral,intraduodenal routes, etc. Generally, the compounds of the presentinvention are administered in single (e.g., once daily) or multipledoses or via constant infusion.

The compositions of this invention comprising a compound of formula I incombination with an NHE-1 inhibitor are useful, for example, in reducingor minimizing damage effected directly to any tissue that may besusceptible to ischemia/reperfusion injury (e.g., heart, brain, lung,kidney, liver, gut, skeletal muscle, retina) as the result of anischemic event (e.g., myocardial infarction). The composition istherefore usefully employed prophylactically to prevent, i.e.(prospectively or prophylactically) to blunt or stem, tissue damage(e.g., myocardial tissue) in patients who are at risk for ischemia(e.g., myocardial ischemia).

Generally, a compouned of formula I of this invention is administeredorally, or parenterally (e.g., intravenous, intramuscular, subcutaneousor intramedullary). Topical administration may also be indicated, forexample, where the patient is suffering from gastrointestinal disordersor whenever the medication is best applied to the surface of a tissue ororgan as determined by the attending physician.

The amount and timing of compounds administered will, of course, bedependent on the subject being treated, on the severity of theaffliction, on the manner of administration and on the judgement of theprescribing physician. Thus, because of patient to patient variability,the dosages given below are a guideline and the physician may titratedoses of the drug to achieve the treatment that the physician considersappropriate for the patient. In considering the degree of treatmentdesired, the physician must balance a variety of factors such as age ofthe patient, presence of preexisting disease, as well as presence ofother diseases.

Thus, for example, in one mode of administration the compounds offormula I of this invention may be administered just prior to surgery(e.g., within twenty-four hours before surgery for example cardiacsurgery) during or subsequent to surgery (e.g., within twenty-four hoursafter surgery) where there is risk of myocardial ischemia. The compoundsof formula I of this invention may also be administered in a chronicdaily mode.

The compounds of the present invention are generally administered in theform of a pharmaceutical composition comprising at least one of thecompounds of, formula I of this invention together with apharmaceutically acceptable vehicle or diluent. Thus, the compounds offormula I of this invention can be administered individually or togetherin any conventional oral, parenteral, rectal or transdermal dosage form.

For purposes of transdermal (e.g., topical) administration, dilutesterile, aqueous or partially aqueous solutions (usually in about 0.1%to 5% concentration), otherwise similar to the above parenteralsolutions, are prepared.

Methods of preparing various pharmaceutical compositions with a certainamount of active ingredient are known, or will be apparent in light ofthis disclosure, to those skilled in this art. For examples of methodsof preparing pharmaceutical compositions, see Remington's PharmaceuticalSciences, Mack Publishing Company, Easton, Pa., 19th Edition (1995).

Pharmaceutical compositions according to the invention may contain forexample 0.0001%-95% of the compound(s) of this invention. In any event,the composition or formulation to be administered will contain aquantity of a compound(s) according to the invention in an amounteffective to treat the disease/condition of the subject being treated.

The two different compounds of this combination of this invention can beco-administered simultaneously or sequentially in any order, or as asingle pharmaceutical composition comprising a compound of Formula I andan aldose reductase inhibitor as described above or a glycogenphosphorylase inhibitor as described above or a cardiovascular agent.

Since the present invention has an aspect that relates to the treatmentof the disease/conditions described herein with a combination of activeingredients which may be administered separately, the invention alsorelates to combining separate pharmaceutical compositions in kit form.The kit comprises two separate pharmaceutical compositions: a compoundof Formula I a prodrug thereof or a salt of such compound or prodrug anda second compound as described above. The kit comprises means forcontaining the separate compositions such as a container, a dividedbottle or a divided foil packet. Typically the kit comprises directionsfor the administration, of the separate components. The kit form isparticularly advantageous when the separate components are preferablyadministered in different dosage forms (e.g., oral and parenteral), areadministered at different dosage intervals, or when titration of theindividual components of the combination is desired by the prescribingphysician.

An example of such a kit is a so-called blister pack. Blister packs arewell known in the packaging: industry and are being widely used for thepackaging of pharmaceutical, unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a preferably transparent plasticmaterial. During the packaging process recesses are formed in theplastic foil. The recesses have the size and shape of the tablets orcapsules to be packed. Next, the tablets or capsules are placed in therecesses and the sheet of relatively, stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are sealed in the recesses between the plastic foil and thesheet. Preferably the strength of the sheet is such that the tablets orcapsules can be removed from the blister pack by manually applyingpressure on the recesses whereby an opening is formed in the sheet atthe place of the recess. The tablet or capsule can then be removed viasaid opening.

It may be desirable to provide a memory aid on the kit, e.g., in theform of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the tablets or capsules sospecified should be ingested. Another example of such a memory aid is acalendar printed on the card, e.g., as follows “First Week, Monday,Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . ” etc.Other variations of memory aids will be readily apparent. A “daily dose”can be a single tablet or capsule or several pills or capsules to betaken on a given day. Also, a daily dose of Formula I compound canconsist of one tablet or capsule while a daily dose of the secondcompound can consist of several tablets or capsules and vice versa. Thememory aid should reflect this.

In another specific embodiment of the invention, a dispenser designed todispense the daily doses one at a time in the order of their intendeduse is provided. Preferably, the dispenser is equipped with amemory-aid, so as to further facilitate compliance with the regimen. Anexample of such a memory-aid is a mechanical counter which indicates thenumber of daily doses that has been dispensed. Another example of such amemory-aid is a battery-powered micro-chip memory coupled with a liquidcrystal readout, or audible reminder signal which, for example, readsout the date that the last daily dose has been taken and/or reminds onewhen the next dose is to be taken.

The compounds of formula I of this invention generally will beadministered in a convenient formulation. The following formulationexamples are illustrative only and are not intended to limit the scopeof the present invention.

In the formulations which follow, “active ingredient” means acompound(s) of this invention. Formulation 1: Gelatin Capsules Hardgelatin capsules are prepared using the following: Ingredient Quantity(mg/capsule) Active ingredient 0.25-100  Starch, NF  0-650 Starchflowable powder  0-50 Silicone fluid 350 centistokes  0-15

A tablet formulation is prepared using the ingredients below:Formulation 2: Tablets Ingredient Quantity (mg/tablet) Active ingredient0.25-100  Cellulose, microcrystalline 200-650 Silicon dioxide, fumed 10-650 Stearate acid  5-15

The components are blended and compressed to form tablets.

Alternatively, tablets each containing 0.25-100 mg of active ingredientsare made up as follows: Formulation 3: Tablets Ingredient Quantity(mg/tablet) Active ingredient 0.25-100 Starch 45 Cellulose,microcrystalline 35 Polyvinylpyrrolidone (as 10% solution in water) 4Sodium carboxymethyl cellulose 4.5 Magnesium stearate 0.5 Talc 1

The active ingredient, starch, and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granules so produced aredried at 50°-60° C., and passed through a No. 18 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate, and talc, previouslypassed through a No. 60 U.S. sieve, are then added to the granuleswhich, after mixing, are compressed on a tablet machine to yieldtablets.

Suspensions each containing 0.25-100 mg of active ingredient per 5 mldose are made as follows: Formulation 4: Suspensions Ingredient Quantity(mg/5 ml) Active ingredient 0.25-100 mg Sodium carboxymethyl cellulose50 mg Syrup 1.25 mg Benzoic acid solution 0.10 mL Flavor q.v. Color q.v.Purified Water to 5 mL

The active ingredient is passed through a No. 45 mesh U.S. sieve andmixed with the sodium carboxymethyl cellulose and syrup to form smoothpaste. The benzoic acid solution, flavor, and color are diluted withsome of the water and added, with stirring. Sufficient water is thenadded to produce the required volume. An aerosol solution is preparedcontaining the following ingredients: Formulation 5: Aerosol IngredientQuantity (% by weight) Active ingredient 0.25 Ethanol 25.75 Propellant22 (Chlorodifluoromethane) 74.00

The active ingredient is mixed with ethanol and the mixture added to aportion of the propellant 22, cooled to 30° C., and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted with the remaining propellant. The valve units arethen fitted to the container.

Suppositories are prepared as follows: Formulation 6: SuppositoriesIngredient Quantity (mg/suppository) Active ingredient 250 Saturatedfatty acid glycerides 2,000

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimal necessary heat. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

An intravenous formulation is prepared as follows: Formulation 7:Intravenous Solution Ingredient Quantity Active ingredient 25 mg-10,000mg Isotonic saline 1,000 mL

The solution of the above ingredients is intravenously administered to apatient.

The active ingredient above may also be a combination of agents.

GENERAL EXPERIMENTAL PROCEDURES

Melting points were determined on a ThomasHoover capillary melting pointapparatus, and are uncorrected. ¹H NMR spectra were obtained on a BrukerAM-250 (Bruker Co., Billerica, Mass.), a Bruker AM-300, a Varian XL-300(Varian Co., Palo Alto, Calif.), or a Varian Unity 400 at about 23° C.at 250, 300, or 400 MHz for proton. Chemical shifts are reported inparts per million (8) relative to residual chloroform (7.26 ppm),dimethylsulfoxide (2.49 ppm), or methanol (3.30 ppm) as an internalreference. The peak shapes and descriptors for the peak shapes aredenoted as follows: s, singlet; d, doublet; t, triplet; q, quartet; m,multiplet; c, complex; br, broad; app, apparent. Low-resolution massspectra were obtained under thermospray (TS) conditions on a Fisons (nowMicromass) Trio 1000 Mass Spectrometer (Micromass Inc., Beverly, Mass.),under chemical-ionization (CI) conditions on a Hewlett Packard 5989AParticle Beam Mass Spectrometer (Hewlett Packard Co., Palo Alto,Calif.), or under atmospheric pressure chemical ionization (APCI) on aFisons (now Micromass) Platform II Spectrometer. Optical rotations wereobtained on a Perkin-Elmer 241 MC Polarimeter (Perkin-Elmer, Norwalk,Conn.) using a standard path length of 1 dcm at about 23° C. at theindicated concentration in the indicated solvent.

Liquid column chromatography was performed using forced flow (flashchromatography) of the indicated solvent on either Baker Silica Gel (40μm, J. T. Baker, Phillipsburg, N.J.) or Silica Gel 60 (EM Sciences,Gibbstown, N.J.) in glass columns or using low nitrogen or air pressurein Flash 40™ or Flash 12™ (Biotage, Charlottesville, Va.) cartridges.Radial chromatography was performed using a Chromatron (HarrisonResearch, Palo Alto, Calif.). The terms “concentrated” and “evaporated”refer to removal of solvent using a rotary evaporator at water aspiratorpressure or at similar pressures generated by a Büchi B-171 Vacobox(Brinkmann Instruments, Inc., Westbury, N.Y.) or a Büchi B-177 Vacoboxwith a bath temperature equal to or less than 50° C. Reactions requiringthe use of hydrogen gas at pressures greater than 1 atmosphere were runusing a Parr hydrogen apparatus (Parr Instrument Co., Moline, Ill.).Unless otherwise specified, reagents were obtained from commercialsources. The abbreviations “d”, “h”, and “min” stand for “day(s)”,“hour(s)”, and “minute(s)”, respectively.

Example 1

(R)-1-[4-(4-Quinoxalin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethanol.

Step A:(R)-1-[4-(4-Quinoxalin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethylacetate. To a solution of (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl acetate(prepared according to the method of Preparation Five, 7.3 g, 36.2 mmol)in isopropanol (240 mL) was added triethylamine (10.1 mL, 72.4 mmol)followed by 2-(1-piperazinyl)quinoxaline (10.1 g, 47.1 mmol; J. Med.Chem. 1981, 24, 93). This mixture was stirred at room temperatureovernight then concentrated. The residue was diluted with saturatedaqueous sodium bicarbonate and extracted with chloroform (5×). Thecombined organic extracts were dried over sodium sulfate, filtered,evaporated, and purified by flash column chromatography (2%methanol/chloroform) to give 12.4 g (91%) of the title compound ofExample 1, Step A as a yellow foam. ¹H NMR (CDCl₃, 250 MHz) δ 8.61 (s,1H), 8.27 (d, 1H), 7.91 (dd, 1H), 7.72 (dd, 1H), 7.61 (td, 1H), 7.44(td, 1H), 6.43 (d, 1H), 5.70 (q, 1H), 3.96-3.84 (c, 8H), 2.18 (s, 3H),1.61 (d, 3H); MS (CI/NH₃) 379 (MH⁺).

Step B:(R)-1-[4-(4-Quinoxalin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethanol. Toa solution of(R)-1-[4-(4-quinoxalin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethylacetate (prepared according to the method of Example 1, Step A, 14.1 g,37.2 mmol) in a 3:1:1 mixture of tetrahydrofuran/water/methanol (375 mL)was added lithium hydroxide hydrate (4.7 g, 112 mmol). This mixture wasstirred at room temperature for 1 h 45 min, concentrated, and extractedwith chloroform (6×). The combined organic extracts were dried oversodium sulfate, filtered, evaporated, and purified by flash columnchromatography (2×; 2% methanol/chloroform) to give 11.3 g (90%) of thetitle compound as a pale yellow solid after tritration with hexanes. mp:106.5-108° C.; ¹H NMR (CDCl₃, 250 MHz) δ 8.62 (s, 1H), 8.26 (d, 1H),7.92 (dd, 1H), 7.72 (dd, 1H), 7.61 (td, 1H), 7.44 (td, 1H), 6.45 (d,1H), 4.75 (m, 1H), 3.95-3.85 (c, 8H), 1.54 (d, 3H); MS (CI/NH₃) 337(MH⁺); [α]_(D) +15.3 (c 2.3, MeOH).

Example 2

(R)-1-[4-(4-oxazolo[5,4-c]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethanol.

Step A:(R)-1-[4-(4-Oxazolo[5,4-c]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethylbutyrate. To a solution of 2-(1-piperazinyl)oxazolo[5,4-c]pyridine (775mg, 3.8 mmol; J. Org. Chem. 1995, 60, 5721) in isopropanol (38 mL) wasadded (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl, butyrate (preparedaccording to the method of Preparation Seven, 868 mg, 3.8 mmol) followedby triethylamine (1.6 mL, 11.4 mmol). This mixture was stirred at refluxovernight, cooled to room temperature, and evaporated. The residue wasdiluted with saturated aqueous sodium bicarbonate and extracted withchloroform (3×). The combined organic extracts were dried over sodiumsulfate, filtered, evaporated, and purified by flash columnchromatography (2×; 3% methanol/chloroform then 68% methanol/ethylacetate, where used herein, the arrow symbol, A, indicates a gradient)to give 1.2 g (79%) of the title compound of Example 2, Step A as a paleyellow oil which solidified upon standing. ¹H NMR (CDCl₃, 250 MHz) δ8.57 (s, 1H), 8.39 (d, 1H), 8.28 (d, 1H), 7.30 (d, 1H), 6.44 (d, 1H),5.70 (q, 1H), 3.85 (s, 8H), 2.42 (t, 2H), 1.78-1.61 (c, 2H), 1.60 (d,3H), 0.98<t, 3H); MS (APCI) 397 (MH⁺).

Step B:(R)-1-[4-(4-Oxazolo[5,4-c]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethanol.To a solution of(R)-1-[4-(4-oxazolo[5,4-c]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethylbutyrate (prepared according to the method of Example 2, Step A, 1.2 g,3.0 mmol) in methanol (30 mL) was added potassium carbonate (823 mg, 6.0mmol). This mixture was stirred at room temperature for 5 h, dilutedwith saturated aqueous ammonium chloride, concentrated, and extractedwith chloroform (3×). The combined organic extracts were dried oversodium sulfate, filtered, evaporated, and purified by flash columnchromatography (6% methanol/chloroform) to give 915 mg (94%) of thetitle compound as a white solid after tritration with hexanes. mp:181-183° C.; ¹H NMR (CDCl₃, 300 MHz) δ 8.54 (d, 1H), 8.35 (d, 1H), 8.25(d, 1H), 7.27 (dd, 1H), 6.44 (d, 1H), 4.71 (q, 1H), 4.25 (br s, 1H),3.86-3.83 (c, 8H), 1.50 (d, 3H); MS (APCI) 327 (MH⁺); [α]_(D) +15.3 (c0.5, MeOH).

Example 3

1R-(4-{1′-[2-(1R-Hydroxy-ethyl)-pyrimidin-4-yl]-[4,4′]bipiperidinyl-1-yl}-pyrimidin-2-yl)-ethanol.

A mixture of (R)-1-(4-chloro-pyrimidin-2-yl)-ethanol (prepared accordingto the method of Preparation Ten, 100 mg, 0.63 mmol), 4,4′-bipiperidinedihydrochloride (76 mg, 0.32 mmol), and triethylamine (0.44 mL, 3.2mmol) in isopropanol (3 mL) was refluxed overnight and cooled to roomtemperature. The reaction mixture was diluted with saturated aqueoussodium bicarbonate and extracted with chloroform (4×). The combinedorganic extracts were dried over sodium sulfate, filtered, evaporated,and purified by flash column chromatography (Biotage Flash 40S™. 5%methanol/chloroform) to give 110 mg (85%) of the title compound as awhite solid. mp: 144-153° C., ¹H NMR (CDCl₃, 400 MHz) δ 8.14 (d, 2H),6.36 (d, 2H), 4.67 (q, 2H), 4.53-4.28 (c, 4H), 2.84 (t, 4H), 1.82 (d,4H), 1.49 (d, 6H), 1.43-1.40 (c, 2H), 1.30-1.18 (c, 4H); MS (APCI) 413(MH⁺); [α]_(D) +22.6 (c 1.0, MeOH).,

Examples 4 to 8

Examples 4 to 8 were prepared from the appropriate starting materials ina manner analogous to the method of Example 3.

Example 4

1R-(4-{4-[2-(1R-Hydroxy-ethyl)-pyrimidin-4-yl]-2R,S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol.

mp: 153-155° C., ¹H NMR (CDCl₃, 400 MHz) δ 8.23 (d, 2H), 6.40 (d, 2H),4.71 (m, 2H), 4.28 (dd, 2H), 3.51-3.45 (c, 4H), 1.51 (d, 6H), 1.23 (d,6H); MS (APCI) 359 (MH⁺); [α]_(D) +18.6 (c 1.2, CHCl₃).

Example N-linker-N mp (° C.) MS (MH⁺) 5 N,N′-ethylenediamine 141-143 3336 [1,4]diazepine 136-138 345 7 4,4′-ethylenebipiperidine 441 8methyl-piperidin-4-ylmethyl-amine 373

Example 9

(R)-1-[4-(4-Oxazolo[5,4-b]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethanol.

Step A: 2-(1-piperazinyl)oxazolo[5,4-b]pyridine. A mixture of2-(thiomethyl)oxazolo[5,4-b]pyridine (9.2 g, 55.5 mmol; J. Org. Chem.1995, 60, 5721) and piperazine (23.9 g, 277 mmol), with a small amountof ethyl acetate which was used for washing the compound down the sidesof the flask, was heated at 90° C. for 1.5 h. The reaction mixture wascooled to room temperature, diluted with ˜20% saturated aqueous sodiumbicarbonate solution, and extracted with chloroform (4×). The combinedorganic extracts were washed with saturated aqueous sodium bicarbonate(1×), dried over sodium sulfate, filtered, evaporated, and purified byflash column chromatography (3→5% methanol/chloroform+1% ammoniumhydroxide) to give 9.1 g (81%) of the title compound of Example 9, StepA as an off-white solid. ¹H NMR (CDCl₃, 300 MHz) δ 7.92 (dd, 1H), 7.55(dd, 1H), 7.10 (dd, 1H), 3.74-3.70 (c, 4H), 3.02-2.97 (c, 4H); MS (APCI)205 (MH⁺).

Step B:(R)-1-[4-(4-Oxazolo[5,4-b]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethylbutyrate. To a solution of (R)-1-(4-chloro-pyrimidin-2-yl)-ethylbutyrate (prepared according to the method of Preparation Seven, 6.8 g,29.9 mmol) and triethylamine (12.5 mL, 89.6 mmol) in isopropanol (100mL) was added 2-(1-piperazinyl)oxazolo[5,4-b]pyridine (preparedaccording to the method of Example 9, Step A, 6.1 g, 29.9 mmol). Thismixture was stirred at reflux overnight, cooled to room temperature, andevaporated. The residue was diluted with saturated, aqueous sodiumbicarbonate and extracted with chloroform (3×). The combined organicextracts were dried over sodium sulfate, filtered, evaporated, andpurified by flash column chromatography (1.52% methanol/chloroform) togive 11.1 g (94%) of the title compound of Example 9, Step B as a yellowoil which solidified upon standing. ¹H NMR (CDCl₃, 250 MHz) δ 8.28 (d,1H), 7.97 (dd, 1H), 7.60 (dd, 1H), 7.25 (dd, 1H), 6.44 (d, 1H), 5.70 (q,1H), 3.85 (app s, 8H), 2.42 (t, 2H), 1.78-1.61 (c, 2H), 1.60 (d, 3H),0.98 (t, 3H); MS (APCI) 397 (MH⁺).

Step C:(R)-1-[4-(4-Oxazolo[5,4-b]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethanol.To a solution of(R)-1-[4-(4-oxazolo[5,4-b]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethylbutyrate (prepared according to the method of Example 9, Step B, 11.0 g,27.6 mmol) in dioxane (11.5 mL) was added concentrated hydrochloric acid(23 mL, 276 mmol). This mixture was stirred at room temperatureovernight, neutralized with 6 N aqueous sodium hydroxide, and extractedwith chloroform (3×). The combined organic extracts were dried oversodium sulfate, filtered, evaporated, and purified by flash columnchromatography (3.5% methanol/chloroform) to give 8.4 g (93%) of thetitle compound as a white solid. mp: 153-156° C.; ¹H NMR (CDCl₃, 300MHz) δ 8.25 (d, 1H), 7.95 (dd, 1H), 7.58 (dd, 1H), 7.15 (dd, 1H), 6.45(d, 1H), 4.72 (q, 1H), 4.25 (br s, 1H), 3.85-3.82 (c, 8H), 1.51 (d, 3H);MS (CI/NH₃) 327 (MH⁺); [α]D+16.1 (c 1.0, MeOH).

Examples 10 to 15

Examples 10 to 15 were prepared from the appropriate starting materialsin a manner analogous to the method of Example 9.

Example X-Ar¹ R¹ mp (° C.) MS (MH⁺) 10 oxazolo[4,5-c]pyridin-2-yl(R)-CH(CH₃)OH 178-180 327 11 oxazolo[5,4-c]pyridin-2-yl —C(CH₃)₂OH181-184 341 12 oxazolo[5,4-c]pyridin-2-yl ±)-CH(CH₃)OH 153-158 327 13oxazolo[5,4-c]pyridin-2-yl (S)-CH(CH₃)OH 175-179 327 14 quinoxalin-2-yl(±)-CH(CH₃)OH 102-105 337 15 (5-iodo)-benzoxazol-2-yl (R)-CH(CH₃)OH 452

Example 16

1R-[4-(3S-Methyl-4-oxazolo[5,4-b]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethanol.

Step A: (S)-2-(4-Benzyl-2-methyl-piperazin-1-yl)-oxazolo[5,4-b]pyridine.A mixture of 2-(thiomethyl)oxazolo[5,4-b]pyridine (44 g, 264 mmol; J.Org. Chem. 1995, 60, 5721) and (S)-1-benzyl-3-methyl-piperazine (25 g,132 mmol; J. Org. Chem. 1995, 60, 4177) was stirred at 130° C. for 3 d,cooled to room temperature, and purified by flash column chromatography(1783% ethyl acetate/hexanes) to give 30 g (74%) of the title compoundof Example 16, Step A as a dark yellow oil. ¹H NMR (CDCl₃, 400 MHz) δ7.89 (d, 1H), 7.53 (d, 1H), 7.34-7.25 (c, 5H), 7.10 (dd, 1H), 4.45 (m,1H), 4.11 (d, 1H), 3.59 (d, 1H), 3.52-3.45 (c, 2H), 2.90 (d, 1H), 2.73(d, 1H), 2.32 (dd, 1H), 2.21 (td, 1H), 1.41 (d, 3H); MS (APCI) 309(MH⁺).

Step B: (S)-2-(2-Methyl-piperazin-1-yl)-oxazolo[5,4-b]pyridine. To asolution of(S)-2-(4-benzyl-2-methyl-piperazin-1-yl)-oxazolo[5,4-b]pyridine(prepared according to the method of Example 16, Step A, 30 g, 97 mmol)in methanol (970 mL) was added hydrogen chloride (5.85 M in methanol, 20mL, 116 mmol), ammonium formate (122 g, 1.95 mol), and 10% palladium oncarbon (60 g, 200 wt %). This mixture was stirred at reflux for 50 min,cooled, and filtered through Celite. The filtrate was concentrated,diluted with saturated aqueous sodium bicarbonate, and extracted withchloroform (1×) followed by 10% isopropanol/chloroform (4×). Thecombined organic extracts were dried over sodium sulfate, filtered, andevaporated to give 16 g (76%) of the title compound of Example 16, StepB as a green oil. ¹H NMR (CDCl₃, 400 MHz) δ 7.89 (m, 1H), 7.53 (m, 1H),7.09 (m, 1H), 4.42 (m, 1H), 4.11 (d, 1H), 3.35 (td, 1H), 3.09-3.03 (c,2H), 2.85 (d, 1H), 2.82 (td, 1H), 1.38 (d, 3H); MS (APCI) 219 (MH⁺).

Step C:1R-[4-(3S-Methyl-4-oxazolo[5,4-b]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethylbutyrate. A mixture of(S)-2-(2-methyl-piperazin-1-yl)-oxazolo[5,4-b]pyridine (preparedaccording to the method of Example 16, Step B, 10 g, 45.9 mmol),(R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according tothe method of Preparation Seven, 9.5 g, 41.7 mmol), and triethylamine(17.3 mL, 125 mmol) in isopropanol (230 mL) was heated at reflux for 30h, cooled to room temperature, diluted with saturated aqueous sodiumbicarbonate, and extracted with chloroform (4×). The combined organicextracts were dried over sodium sulfate, filtered, evaporated, andpurified by flash column chromatography (1.5% methanol/chloroform) togive 16 g (93%) of the title compound of Example 16, Step C as a yellowoil. ¹H NMR (CDCl₃, 400 MHz) δ 8.23 (d, 1H), 7.93 (dd, 1H), 7.57 (d,1H), 7.13 (dd, 1H), 6.39 (d, 1H), 5.67 (q, 1H), 4.61 (m, 1H), 4.42 (m,1H), 4.28 (m, 1H), 4.18 (dt, 1H), 3.51 (td, 1H), 3.41 (dd, 1H), 3.17(td, 1H), 2.39 (t, 2H), 1.72-1.59 (c, 2H), 1.57 (d, 3H), 1.30 (d, 3H),0.95 (t, 3H); MS (APCI) 411 (MH⁺).

Step D:1R-[4-(3S-Methyl-4-oxazolo-[5,4-b]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethanol.A mixture of1R-[4-(3S-methyl-4-oxazolo[5,4-b]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethylbutyrate (prepared according to the method of Example 16, Step C, 16 g,39.0 mmol) and potassium carbonate (10.8 g, 78.1 mmol) in methanol (195mL) was stirred at room temperature for 4 h, diluted with saturatedaqueous sodium bicarbonate, and extracted with chloroform (1×) followedby 10% isopropanol/chloroform (3×). The combined organic extracts weredried over sodium sulfate, filtered, evaporated, and purified by flashcolumn chromatography (12.5% methanol/chloroform) to give a white foamthat was recrystallized from ether/chloroform to give 8.9 g (67%) of thetitle compound as a white solid. mp: 147-149° C.; ¹H NMR (CDCl₃, 400MHz) δ 8.24 (d, 1H), 7.94 (dd, 1H), 7.58 (d, 1H), 7.14 (dd, 1H), 6.42(d, 1H), 4.72 (m, 1H), 4.64 (m, 1H), 4.42 (m, 1H), 4.32 (m, 1H), 4.25(d, 1H), 4.21 (dt, 1H), 3.54 (td, 1H), 3.46 (dd, 1H), 3.24 (td, 1H),1.51 (d, 3H), 1.33 (d, 3H); MS (APCI) 411 (MH⁺); [α]_(D) +70.4 (c 1.1,MeOH).

Examples 17 to 25

Examples 17 to 25 were prepared from the appropriate starting materialsin a manner analogous to the method of Example 16.

Example 17

1R-[4-(3S-Methyl-4-,quinoxalin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethannol.

¹H NMR (CDCl₃, 400 MHz) δ8.56 (d, 1H), 8.23 (d, 1H), 7.89 (d, 1H), 7.69(d, 1H), 7.59 (t, 1H), 7.41 (t, 1H), 6.42 (d, 1H), 4.78 (m, 1H), 4.73(m, 1H), 4.43 (m, 1H), 4.38-4.23 (c, 2H), 3.64-3.52 (c, 2H), 3.38 (m,1H), 1.52 (d, 3H), 1.30 (d, 3H); MS (APCI) 351 (MH⁺); [α]_(D) +57.0 (c1.2, CHCl₃).

Example 18

1R-{4-[4-(4,6-Dimethyl-pyrimidin-2-yl)-3S-methyl-piperazin-1-yl]-pyrimidin-2-yl}ethanol.

¹H NMR (CDCl₃, 400 MHz) δ 8.18 (d, 1H), 6.37 (d, 1H), 6.30 (s, 1H), 5.04(m, 1H), 4.70 (q, 1H), 4.60 (dt, 1H), 4.37 (br s, 1H), 4.36-4.12 (c,2H), 3.40 (dd, 1H), 3.34 (td, 1H), 3.16 (td, 1H), 2.28 (s, 6H), 1.51 (d,3H), 1.16 (d, 3H); MS (APCI) 329 (MH⁺); [α]_(D) +78.8 (c 1.6, MeOH).

Example 19

1R-{4-[4-(2-Hydroxymethyl-6-methyl-pyrimidin-4-yl)-3S-methyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.

¹H NMR (CDCl₃, 400 MHz) δ 8.23 (d, 1H), 6.38 (d, 1H), 6.23 (s, 1H), 4.71(q, 1H), 4.58 (s, 3H), 4.36-4.18 (c, 4H), 3.86 (br s, 1H), 3.57 (dd,1H), 3.46 (td, 1H), 3.32 (td, 1H), 2.38 (s, 3H), 1.51 (d, 3H), 1.22 (d,3H); MS (APCI) 345 (MH⁺); [α]_(D) +72.6 (c 1.1, MeOH).

Example 20

1R-[4-(3S-Methyl-4-oxazolo[4,5-b]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethanol.

-   -   mp: 158-161° C.; ¹H NMR (CDCl₃, 400 MHz) δ 8.22-8.15 (c, 2H),        7.40 (dd, 1H), 6.86 (dd, 1H), 6.40 (d, 1H), 4.65 (m, 1H), 4.61        (m, 1H), 4.44-4.20 (c, 3H), 4.18 (dt, 1H), 3.50 (td, 1H), 3.41        (dd, 1H), 3.19 (td, 1H), 1.45 (d, 3H), 1.26 (d, 3H); MS (APCI)        341 (MH⁺); [α]_(D) +58.2 (c 1.1, MeOH).

Example 21

1R-[4-(3S-Methyl-4-oxazolo[4,5-c]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethanol.

¹H NMR (CDCl₃, 400 MHz) δ 8.68 (d, 1H), 8.32 (d, 1H), 8.24 (d, 1H), 7.25(dd, 1H), 6.42 (d, 1H), 4.71 (m, 1H), 4.60 (m, 1H), 4.42 (m, 1H),4.32-4.23 (c, 2H), 4.17 (dt, 1H), 3.56 (td, 1H), 3.47 (dd, 1H), 3.24(td, 1H), 1.51 (d, 3H), 1.32 (d, 3H); MS (APCI) 341 (MH⁺); [α]D+57.9 (c1.6, MeOH).

Example 22

1R-[4-(3S-Methyl-4-oxazolo[5,4-c]pyridin-2-VI-piperazin-1-yl)-pyrimidin-2-yl]-ethanol.

¹H NMR (CDCl₃, 400 MHz) δ 8.56 (s, 1H), 8.37 (d, 1H), 8.25 (d, 1H), 7.29(d, 1H), 6.43 (d, 1H), 4.72 (m, 1H), 4.65 (m, 1H), 4.45 (m, 1H), 4.29(m, 1H), 4.264.20(c, 2H), 3.58 (td, 1H), 3.48 (dd, 1H), 3.26 (td, 1H),1.51, (d, 3H), 1.34 (d, 3H); MS (APCI) 341 (MH⁺); [α]_(D) +61.1 (c 1.0,MeOH).

mp Example X-Ar¹ C* (° C.) MS (MH⁺) 23 quino0xalin-2-yl R 351 24(2-[C(CH₃)₂OH])-pyrimidin-4-yl S 359 25 benmzoxazol-2-yl S 340

Example 26

1R-(4-{4-[2-(1R-Hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.

Method 1: To a solution of1R-[4-(2R,6S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl butyrate(prepared according to the method of Preparation Four, 72.8 g, 238 mmol)and triethylamine (50 mL, 357 mmol) in isopropanol (793 mL) was added(R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according tothe method of Preparation Seven, 54.3 g, 238 mmol). This mixture wasstirred at reflux for 12 h and concentrated. The residue was dissolvedin a 3:1:1 mixture of tetrahydrofuran/methanol/water (1200 mL) andlithium hydroxide hydrate (60 g, 1.43 mol) was added. This mixture wasstirred at room temperature for 2.5 h, concentrated somewhat, dilutedwith saturated aqueous sodium bicarbonate, and extracted with 10%isopropanol/chloroform (6×). The combined organic extracts were driedover sodium sulfate, filtered, and evaporated. The residue was dilutedwith 1:1 ethyl acetate/methanol (1100 mL) and stirred at roomtemperature for 1 h. The precipitate was collected by filtration and thefiltrate was concentrated to about 850 mL. After 1 h, more precipitatehad formed and this material was collected by filtration. The filtratewas concentrated somewhat and ethyl acetate was added. After 1 h moreprecipitate had again formed and this material was collected byfiltration. This was repeated one more time to give in total 65.9 g(77%) of the title compound as a white solid. mp: 163-164.5° C.; ¹H NMR(CDCl₃, 400 MHz) δ 8.24 (d, 1H), 8.23 (d, 1H), 6.46 (d, 1H), 6.36 (d,1H), 4.74-4.70 (c, 2H), 4.70-4.50 (c, 2H), 4.50-4.30 (c, 2H), 4.30 (d,1H), 4.27 (d, 1H), 3.31 (dt, 2H), 1.51 (d, 6H), 1.26 (d, 6H); MS (APCI)359 (MH⁺); [α]_(D) +42.3 (c 1.0, MeOH).

Method 2, Step A: 1R-(4-{4-[2-(lR-Butyryloxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethylbutyrate. To a solution of (R)-2-(1-butyryloxy-ethyl)-3H-pyrimidin-4-one(828 g, 3.9 mol) in dichloromethane (50 L) was added triethylamine (576mL, 4.1 mol) and the resulting solution was cooled to 50° C. A solutionof trifluoromethanesulfonic anhydride (729 mL, 4.3 mmol) indichloromethane (6 L) was added slowly such that the internaltemperature was maintained at <10° C. After the addition was complete,the reaction was judged complete by TLC and quenched by the addition ofwater (5.3 L). The organic layer was separated, washed with water (20 L)and saturated aqueous sodium bicarbonate (20 L), and dried over sodiumsulfate. This solution was then slowly added to a solution of1R-[4-(2R,6S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl butyratedibenzoyl-L-tartrate salt (prepared according to the method ofPreparation Fifteen, 2.49 kg, 3.75 mol) and triethylamine (1.6 L, 11.6mol) in dimethylacetamide (18 L) such that the internal temperature wasmaintained at <10° C. The resulting solution was allowed to stir for 12h at 10° C. and then diluted with ethyl acetate (40 L) and water (27 L).The aqueous layer was removed and the organic layer was washed twicewith water (40 L) and once with brine (20 L), and dried over sodiumsulfate. The resulting solution was partially concentrated (8 L) andthen hexanes (23 L) was added. The resulting suspension was allowed togranulate for 12 h and then filtered over cotton. The solids were driedunder vacuum (40° C.) to provide 1178 μm (63%) of the title compound ofExample 26, Method 2, Step A as a white solid. The ¹H NMR and MS datafor this compound are in agreement with that of Example 266.

Method 2, Step B:1R-(4-{4-[2-(1R-Hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.To a solution of1R-(4-{4-[2-(1R-butyryloxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethylbutyrate (prepared according to the method of Example 26, Method 2, StepA, 1140 g, 2.28 mol) in isopropanol (11.4 L) was added 40% aqueouspotassium hydroxide (800 mL) at room temperature. The resulting solutionwas allowed to stir for 16 h and then diluted with water (5 L) anddichloromethane (4, L). The organic layer was separated and the aqueouslayer was extracted with dichloromethane (4 L). The combined organiclayers were washed twice with 1 M aqueous sodium hydroxide (10 L) andtwice with water (5 L), partially concentrated (5 L), diluted with ethylacetate (4 L), and again partially concentrated (6 L). Hexanes (10 L)was added and the resulting slurry was allowed to stir at reflux for 12h, cooled to room temperature, and filtered. The resulting solid wasdried under vacuum to provide 758 g (93%) of the title compound as awhite solid. The mp, ¹H NMR, MS, and optical rotation data for thiscompound are in agreement with that of Example 26, Method 1.

Examples 27 to 62

Examples 27 to 62 were prepared from the appropriate starting materialsin a manner analogous to the method of Example 26.

Example 27

1R-{4-[4-(4,6-Dimethyl-pyrimidin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.

mp: 150.5-152° C.; ¹H NMR (CD₃OD, 300 MHz) δ 8.14 (d, 1H), 6.62 (d, 1H),6.46 (d, 1H), 6.40 (s, 1H), 4.83 (d, 2H), 4.72-4.52 (c, 3H), 3.30 (dd,2H), 2.28 (s, 6H), 1.46 (d, 3H), 1.23 (d, 6H); MS (APCI) 343 (MH⁺);[α]_(D) +12.0 (c 1.3, MeOH).

Example 28

1R-[4-(2R,6S-Dimethyl-4-oxazolo[5,4-c]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethanol.

¹H NMR (CD₃OD, 300 MHz) δ 8.53 (d, 1H), 8.28 (d, 1H), 8.20 (d, 1H), 7.34(dd, 1H), 6.68 (d, 1H), 4.90-4.72 (c, 2H), 4.69 (q, 1H), 4.32 (d, 2H),3.56 (dd, 2H), 1.47 (d, 3H), 1.33 (d, 6H); MS (APCI) 343 (MH⁺); [α]_(D)+8.1 (c 1.3, MeOH).

Example 29

1R-[4-[4-(4-Hydroxymethyl-6-methyl-pyrimidin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl]-ethanol.

-   -   mp: 139-141° C.; ¹H NMR (CD₃OD, 300 MHz) δ 8.24 (d, 1H), 6.51        (d, 1H), 6.38 (s, 1H), 4.90 (m, 1H), 4.84 (d, 2H), 4.77-4.53 (c,        2H), 4.55 (s, 2H), 3.24 (dd, 2H), 2.37 (s, 3H), 1.61 (d, 3H),        1.32 (d, 6H); MS (APCI) 359 (MH⁺); [α]_(D) +14.8 (c 1.0, MeOH).

Example 30

1R-{4-[4-(2,6-Dimethyl-pyrimidin-4-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.

¹H NMR (CDCl₃, 300 MHz) δ 8.22 (d, 1H), 6.36 (d, 1H), 6.26 (s, 1H), 4.71(m, 1H), 4.65-4.50 (c, 2H), 4.42-4.28 (c, 3H), 3.24 (dd, 2H), 2.49 (s,3H), 2.35 (s, 3H), 1.52 (d, 3H), 1.26 (d, 6H); MS (APCI) 343 (MH⁺);[α]_(D) +11.4 (c 0.8, MeOH).

Example 31

1R-[4-(2R,6S-Dimethyl-4-oxazolo-[4,5-b]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethanol.

-   -   mp: 231-233° C.; ¹H NMR (CDCl₃, 400 MHz) δ 8.26-8.23 (c, 2H),        7.47 (d, 1H), 6.94 (dd, 1H), 6.39 (d, 1H), 4.75-4.53 (c, ²H),        4.72 (q, 1H), 4.35 (d, 1H), 4.28 (m, 1H), 3.44 (dd, 2H), 1.51        (d; 3H), 1.34 (d, 6H); MS (APCI) 355 (MH⁺); [α]_(D) +8.0 (c 0.8,        MeOH).

Example 32

1R-{4-[4-(2-Hydroxymethyl-6-methyl-pyrimidin-4-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.

¹H NMR (CD₃OD, 300 MHz) δ 8.16 (d, 1H), 6.66 (s, 1H), 6.63 (d, 1H),4.85-4.63 (c, 2H), 4.67 (q, 1H), 4.5.8 (d, 2H), 4.50 (s, 2H), 3.26 (dd,2H), 2.35 (s, 3H), 1.46 (d, 3H), 1.24 (d, 6H); MS (APCI) 359 (MH⁺);[α]_(D) +11.8 (c 0.9, MeOH).

Example 33

1R-[4-(2R,6S-Dimethyl-4-oxazolo[5,4-b]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethanol.

mp: 204-207° C.; ¹H NMR (CDCl₃, 400 MHz) δ 8.25 (d, 1H), 7.95 (dd, 1H),7.59 (dd, 1H), 7.15 (dd, 1H), 6.39 (d, 1H), 4.80-4.57 (c, 2H), 4.73 (q,1H), 4.30 (d, 2H), 3.42 (dd, 2H), 1.51 (d, 3H), 1.35 (d, 6H); MS (APCI)355 (MH⁺); [α]_(D) +7.5 (c 0.7, MeOH).

Example 34

2-(4-{4-[2-(1R-Hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-propan-2-ol.

-   -   mp: 138-140° C.; ¹H NMR (CDCl₃, 400 MHz) δ 8.23 (d, 2H), 6.45        (d, 1H), 6.36 (d, 1H) 4.86 (s, 1H), 4.70 (m, 1H), 4.67-4.33 (c,        4H), 4.30 (d, 1H), 3.31 (dd, 2H), 1.53 (s, 6H), 1.51 (d, 3H),        1.25 (d, 6H); MS (APCI) 373 (MH⁺); [α]_(D) +15.5 (c 1.2, MeOH).

Example 35

1R-{4-[4-(4-Hydroxymethyl-6-methyl-pyrimidin-2-yl)-2S-methyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.

¹H NMR (CDCl₃, 400 MHz) δ 8.18 (d, 1H), 6.36 (d, 1H), 6.32 (s, 1H), 4.69q, 1H), 4.60-4.53 (c, 3H), 4.52 (s, 2H), 4.38-4.18 (c, 2H), 3.63 (m,1H), 3.40-3.29 (c, 2H), 3.24 (m, 1H), 2.32 (s, 3H), 1.49 (d, 3H), 1.20(d, 3H); MS (APCI) 345 (MH⁺); [α]_(D) +66.5 (c 1.0, MeOH).

Example 36

1R-{4-[4-(4-Hydroxymethyl-6-methyl-pyrimidin-2-yl)-2R-methyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.

¹H NMR (CDCl₃, 400 MHz) δ 8.21 (d, 1H), 6.37 (d, 1H), 6.33 (s, 1H), 4.72(m, 1H), 4.67-4.54 (c, 3H), 4.54 (s, 2H), 4.34 (d, 1H), 4.20 (d, 1H),3.58 (br s, 1H), 3.42-3.32 (c, 2H), 3.26 (td, 1H), 2.34 (s, 3H), 1.51(d, 3H), 1.21 (d, 3H); MS (APCI) 345 (MH⁺); [α]_(D) −35.0 (c 1.1, MeOH).

Example 37

1R-{4-[4-(2-Hydroxymethyl-pyrimidin-4-yl)-3S-methyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.

mp: 178-181° C.; ‘H’ NMR (CDCl₃, 400 MHz) δ 8.23 (d, 2H), 6.38 (d, 2H),4.60(q, 1H), 4.60 (s, 12H), 4.56 (m, 1H), 4.28-4.15 (c, 4H), 3.72 (br s,1H), 3.58 (dd, 1H), 3.48 (m, 1H), 3.33 (td, 1H), 1.51 (d, 3H), 1.23 (d,3H); MS (APCI) 331 (MH⁺); [α]_(D) +88.9 (c 1.1, MeOH).

Example 38

1R-(4-{4-[2-(1R-Hydroxy-ethyl)-pyrimidin-4-yl]-2S-methyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol.

mp: 158-160° C.; ¹H NMR (CDCl₃, 400 MHz) δ 8.24 (d, 2H), 6.39 (d, 1H),6.38 (d, 1H), 4.71 (m, 2H), 4.55 (br s, 1H), 4.32-4.16 (c, 5H), 3.60(dd, 1H), 3.48 (td, 1H), 3.38 (td, 1H), 1.52 (d, 6H), 1.24 (d, 3H); MS(APCI) 345 (MH⁺); [α]_(D) +82.5 (c 1.0, MeOH).

Example 39

1R-(4-{4-[2-(1R-Hydroxy-ethyl)-pyrimidin-4-yl]-2R-methyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol.

mp: 155-157° C.; ¹H NMR (CDCl₃, 400 MHz) δ 8.24 (d, 2H), 6.39 (d, 1H),6.38 (d, 1H), 4.73 (m, 2H), 4.58 (brs, 1H), 4.32-4.16 (c, 5H), 3.59 (dd,1H), 3.50 (m, 1H), 3.38 (m, 1H), 1.52 (d, 6H), 1.25 (d, 3H); MS (APCI)345 (MH⁺); [α]_(D) −30.4 (c 0.9, MeOH).

Example 40

1R-(4-{3-[2-(1R-Hydroxy-ethyl)-pyrimidin-4-yl]-3,9-diaza-bicyclo[3.3.1]non-9-yl}-pyrimidin-2-yl)-ethanol.

mp: 151-158° C.; ¹H NMR (CDCl₃, 400 MHz) δ 8.24 (d, 2H), 6.42 (d, 1H),6.411 (d, 1H), 4.72 (m, 2H), 4.48-4.18 (c, 2H), 4.29 (dd, 2H), 3.28 (d,2H), 2.03 (m, 1H), 1.98-1.82 (c, 4H), 1.58 (m, 1H), 1.51 (d, 3H), 1.50(d, 3H); MS (APCI) 371 (MH⁺); [α]_(D) +27.6 (c 0.9, MeOH).

Example 41

1R-(4-[4-[2-(1S-Hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl)-ethanol.

mp: 222-223.5° C.; ¹H NMR (CDCl₃, 400 MHz) δ 8.24 (d, 1H), 8.23 (d, 1H),6.46 (d, 1H), 6.36 (d, 1H), 4.75-4.51 (c, 4H), 4.50-4.30 (c, 4H), 3.31(dt, 2H), 1.51 (d, 6H), 1.26 (d, 6H); MS (APCI) 359 (MH⁺); [α]_(D) −3.4(c 0.5, CHCl₃).

Example 42

1S-(4-{4-[2-(1R-Hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.

mp: 224-226° C.; ¹H NMR (CDCl₃, 400 MHz) δ 8.24 (d, 1H), 8.23 (d, 1H),6.46 (d, 1H), 6.36 (d, 1H), 4.76-4.51 (c, 4H), 4.50-4.23 (c, 4H), 3.33(dt, 2H), 1.51 (d, 6H), 1.25 (d, 6H); MS (APCI), 359 (MH⁺); [α]D+64.2 (c0.5, CHCl₃).

Example 43

1S-(4-{4-[2-(1S-Hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol.

mp: 164-165.5, ° C.; ¹H NMR (CDCl₃, 400 MHz) δ 8.24 (d, 1H), 8.23 (d,1H), 6.46 (d, 1H), 6.36 (d, 1H), 4.75-4.51 (c, 4H), 4.50-4.23 (c, 4H),3.47-3.28 (c, 2H), 1.51 (d, 6H), 1.25 (d, 6H); MS (APCI) 359 (MH⁺);[α]_(D) −43.8 (c 1.0, MeOH).

Example 44

1RS-(4-{4-[2-(1RS-Hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin1-yl}-pyrimidin-2-yl)-ethanol.

mp: 180-186° C.; ¹H NMR (CDCl₃, 400 MHz) 58.24 (d, 1H), 8.23 (d, 1H),6.486 (d, 1H), 6.36 (d, 1H), 4.75-4.51 (c, 4H), 4.50-4.23 (c, 4H),3.47-3.28 (c, 2H), 1.51 (d, 6H), 1.25 (d, 6H); MS (APCI) 359(MH⁺).

Example 45

1-(4-{4-[2-(1R-Hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl-pyrimidin-2-yl}-ethanone.

mp: 123-127° C.; ¹H NMR (CDCl₃, 400 MHz) δ 8.41 (d, 1H), 8.24 (d, 1H),6.56 (d, 1H), 6.47 (d, 1H), 4.75-4.53 (c, 3H), 4.52-4.28 (c, 2H), 4.26(m, 1H), 3.36-3.29 (c, 2H), 2.68 (s, 3H), 1.51 (d, 3H), 1.28 (d, 6H); MS(APCI) 357 (MH⁺); [α]_(D) +19.4 (c 1.0, MeOH).

Example 46

1-(4-{4-[2-(1R-Hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanone.

mp: 150-164° C.; ¹H NMR (CDCl₃, 400 MHz) δ 8.40 (d, 1H), 8.24 (d, 1H),6.66 (d, 1H), 6.37 (d, 1H), 4.74-4.52 (c, 3H), 4.51-4.31 (c, 2H), 4.29(m, 1H), 3.36 (dd, 2H), 2.69 (s, 3H), 1.51 (d, 3H), 1.27 (d, 6H); MS(APCI) 357 (MH⁺); [α]_(D) +21.8 (c 1.1, MeOH).

Example 47

1R-(4-{4-[2-(1R-Hydroxy-ethyl)-pyrimidin-4-yl]-2R,6R-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol.

mp: 168-171° C.; ¹H NMR (CDCl₃, 400 MHz) δ 8.27 (d, 1H), 8.23 (d, 1H),6.33 (d, 1H), 6.30 (d, 1H), 4.78-4.69 (c, 2H), 4.68-4.28 (c, 5H),3.83-3.69 (c, 2H), 3.54 (m, 1H), 1.53 (d, 3H), 1.52 (d, 3H), 1.43-1.22(c, 6H); MS (APCI) 359 (MH⁺); [α]_(D) +92.2 (c 0.5, MeOH).,

Example 48

1R-(4-{4-[2-(1R-Hydroxy-ethyl)-pyrimidin-4-yl]-2S,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol.

mp: 168-178° C.; ¹H NMR (CDCl₃, 400 MHz) δ 8.26 (d, 1H), 8.23 (d, 1H),6.32 (d, 1H), 6.29 (d, 1H), 4.78-4.68 (c, 2H), 4.65-4.27 (c, 5H),3.82-3.71 (c, 2H), 3.55 (m, 1H), 1.52 (d, 3H), 1.51 (d, 3H), 1.43-1.20(c, 6H); MS (APCI) 359 (MH⁺); [α]_(D) −32.4 (c 0.7, MeOH).

Example X-Ar¹ R²⁶ R⁷ mp (° C.) MS (MH⁺) 49 benzoxaol-2-yl (R)-Me (S)-Me354 50 benzothiazol-2-yl (R)-Me (S)-Me 370 51 oxazolo[4,5-c]pyridin-2-yl(R)-Me (S)-Me 355 52 quinoxalin-2-yl (R)-Me H 351 53 quinoxalin-2-yl(S)-Me H 351 54 quinoxalin-2-yl (R)-Me (S)-Me 365 55 (4,6-dimethyl)- H H132-133 315 pyrimidin-2-yl 56 (4,6-dimethyl)- (S)-Me H 329pyrimidin-2-yl 57 (2,6-dimethyl)- H H 125.5-127   314 pyrimidin-4-yl 58(2-hydroxymethyl)- (S)-Me H 146-148 331 pyrimidin-4-yl 59(2-hydroxymethyl)- (R)-Me (S)-Me 168-171 345 pyrimidin-4-yl 60(2-hydroxymethyl-6- (S)-Me H 345 methyl)-pyrimidin-4-yl

Example X-Ar¹ mp (° C.) MS (MH⁺) 61 (4-hydroxymethyl-6- 357methy)-lpyrimidin-2-yl 62 (R)-[2-(1-hydroxy-ethyl)]- 357 pyrimidin-4-yl

Example 63+

1-{4-[4-(2-Acetyl-pyrimidin-4-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanone.

A mixture of1S-(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol(prepared according to the method of Example 42, 1.05 g, 2.93 mmol) andmanganese(IV) oxide (5.15 g, 59.3 mmol) in dichloroethane (28 mL) washeated at reflux for 7 h, and filtered through Celite (hot). Thefiltrate was concentrated and purified by flash column chromatography(Flash 40M™, 5% methanol/chloroform) to give 0.67 g (64%) of the titlecompound as a white solid. mp: >235° C. (dec); ¹H NMR (CDCl₃, 400 MHz) δ8.42 (d, 1H), 8.41 (d, 1H), 6.68 (d, 1H), 6.57 (d, 1H), 4.81-4.36 (c,4H), 3.39 (dd, 2H), 2.69 (s, 3H), 2.68 (s, 3H), 1.29 (d, 6H); MS (APCI)355 (MH⁺).

Example 64

1R-{4-[4-(4-Hydroxymethyl-6-methyl-pyrimidin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.

Step A:1R-{4-[4-(tert-Butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethytbutyrate.To a mixture of1R-[4-(3R,5S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl butyrate(prepared according to the method of Preparation Three, 10 g, 32.7mmol), N,N′-bis(tert-butoxycarbonyl)thiourea (8.6 g, 32.7 mmol; Synth.Commun. 1993, 23, 1443), and triethylamine (9.0 mL, 65.4 mmol) indimethylformamide (110 mL) at 0° C. was added mercury(II) chloride (9.8g, 36.0 mmol). This mixture was stirred overnight with warming to roomtemperature, diluted with ethyl acetate, and washed with water (3×) andbrine (1×). The organic phase was dried over sodium sulfate, filtered,and evaporated to give 17.9 g (100%) of the title compound of Example64, Step A as a yellow foam. ¹H NMR (CDCl₃, 300 MHz) δ 9.61 (s, 1H),8.19 (d, 1H), 6.37 (d, 1H), 5.66 (q, 1H), 4.51-4.14 (c, 4H), 3.36-3.23(c, 2H), 2.37 (t, 2H), 1.75-1.60 (c, 2H), 1.55 (d, 3H), 1.49 (s, 9H),1.46 (s, 9H), 1.28 (d, 3H), 1.26 (d, 3H), 0.94 (t, 3H); MS (APCI) 549(MH⁺).

Step B:1R-[4-(4-Carbamimidoyl-3R,5S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethylbutyrate trifluoroacetic acid salt. A mixture of1R-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethylbutyrate (prepared according to the method of Example 64, Step A, 17.9g, 32.7 mmol) in a 3:1 mixture of dichloromethane/trifluoroacetic acid(300 mL) was stirred at room temperature overnight and concentrated toprovide 36 g of the title compound of Example 64, Step B as an oil thatwas used as is. ¹H NMR (CD₃OD, 400 MHz) δ 8.24 (d, 1H), 7.25 (d, 1H),5.69 (q, 1H), 4.19-4.10 (c, 4H), 3.79-3.42 (c, 2H), 2.45 (t, 2H),1.67-1.45 (c, 2H), 1.63 (d, 3H), 1.32-1.25 (c, 6H), 0.95 (t, 3H); MS(APCI) 349, (MH⁺).

Step C:1R-{4-[4-(4-Methoxymethyl-6-methyl-pyrimidin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.A solution of 1 M sodium isopropoxide in isopropanol was prepared byadding sodium metal (3.8 g, 160 mmol) to isopropanol (160 mL) andheating at reflux until all the metal was consumed.1R-[4-(4-Carbamimidoyl-3R,5S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethylbutyrate trifluoroacetic acid salt (prepared according to the method ofExample 64, Step B, 32.7 mmol theory) was added to the refluxing sodiumisopropoxide/isopropanol solution followed, after 1 h, by1-methoxy-pentane-2,4-dione (21.2 g, 163 mmol; J. Am. Chem. Soc. 1944,22, 2092). After 12 h, another aliquot of sodium isopropoxide (1 M inisopropanol, 65 mL, 65 mmol) was added. After refluxing overnight, thereaction mixture was cooled to room temperature and diluted with water(100 mL). Lithium hydroxide hydrate (6.9 g, 163 mmol) was added and thismixture was stirred for 3 h, concentrated, and extracted with 10%isopropanol/chloroform (3×). The combined organic extracts were driedover sodium sulfate, filtered, evaporated, and purified by flash columnchromatography (12.5% methanol/chloroform) to give 10.5 g (87%, 2 steps)of the title compound of Example 64, Step C as a yellow solid. ¹H NMR(CDCl₃, 400 MHz) δ 8.18 (d, 1H), 6.54 (s, 1H), 6.43 (d, 1H), 5.00-4.94(c, 2H), 4.69 (m, 1H), 4.37-4.34 (c, 2H), 4.33 (s, 2H), 3.45 (s, 3H),3.29-3.23 (c, 2H), 2.33 (s, 3H), 1.51 (d, 3H), 1.20 (s, 6H); MS (APCI)373 (MH⁺).

Step D:1R-{4-[4-(4-Hydroxymethyl-6-methyl-pyrimidin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.To a solution of 1R-{4-[4-(4-methoxymethyl-6-methyl-pyrimidin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol (prepared accordingto the method of Example 64, Step C, 8.0 g, 21.5 mmol) indichloromethane (150 mL) at 0° C. was added boron tribromide (1 M indichloromethane, 64.3 mL, 64.3 mmol). This mixture was stirred overnightwith warming to room temperature and quenched by careful addition ofsaturated aqueous sodium bicarbonate. The layers were separated and theaqueous phase was extracted with 10% isopropanol/chloroform (3×). Thecombined organic extracts were washed with brine, (1×), dried oversodium sulfate, filtered, and evaporated. The resulting solid wasrefluxed in ethyl acetate and filtered (hot). This procedure wasrepeated and the combined filtrates were concentrated to a minimalvolume. After standing at room temperature overnight, a tan solid wascollected by filtration. The resulting filtrate was again allowed tostand at room temperature overnight to yield an additional crop of theedesired product to give all together 6.0 g (78%) of the title compoundas a tan solid. mp: 149-151° C.; ¹H NMR (CDCl₃, 400 MHz) δ 8.19 (d, 1H),6.45 (d, 1H), 6.32 (s, 1H), 5.02-4.96 (c, 2H), 4.71 (q, 1H), 4.53 (s,2H), 4.50-4.23 (c, 2H), 3.3 μl-3.25 (c, 2H), 2.33 (s, 3H), 1.51 (d, 3H),1.23 (s, 6H); MS (APCI) 359 (MH⁺); [α]_(D) +18.9 (c 1.1, MeOH).

Examples 65 to 74

Examples 65 to 74, were prepared from the appropriate starting materialsin a manner analogous to the method of Example 64.

Example 65

(R)-1-[4-[4-(4-Hydroxymethyl-6-methyl-pyrimidin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl-ethanol.

mp: 139-140° C.; ¹H NMR (CDCl₃, 300 MHz) δ 8.21 (d, 1H), 6.41 (d, 1H),6.37 (s, 1H), 4.71 (m, 1H), 4.54 (s, 2H), 4.32 (d, 1H), 4.02-3.93 (c,4H), 3.78-3.68 (c, 4H), 3.65 (br s, 1H), 2.34 (s, 3H), 1.19 (d, 3H); MS(TS) 331 (MH⁺); [α]_(D) +21.6 (c 2.0, MeOH).

Example 66

1R-{4-[4-(4,6-Dimethyl-pyrimidin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.

mp: 141.5-142.5° C.; ¹H NMR (CDCl₃, 400 MHz) δ 8.17 (d, 1H), 6.43 (d,1H), 6.28 (s, 1H), 5.03-4.97 (c, 2H), 4.70 (q, 1H), 4.44-4.18 (c, 2H),3.32-3.20 (c, 2H), 2.27 (s, 6H), 1.50 (d, 3H), 1.20 (d, 6H); MS (APCI)343 (MH⁺); [α]_(D) +19.2 (c 1.1, MeOH).

Example 67

1R-{4-[4-(4-Methoxymethyl-6-methyl-pyrimidin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.

¹H NMR (CDCl₃, 400 MHz) δ 8.18 (d, 1H), 6.55 (s, 1H), 6.43 (d, 1H),5.02-4.93 (c, 2H), 4.69 (m, 1H), 4.43-4.20 (c, 2H), 4.36 (d, 1H), 4.33(s, 2H), 3.46 (s, 3H), 3.30-3.21 (c, 2H), 2.34 (s, 3H), 1.51 (d, 3H),1.20 (d, 6H); MS (APCI) 373 (MH⁺); [α]_(D) +16.0 (c 0.9, MeOH).

Example 68

1R-{4-[4-(4-Hydroxymethyl-6-methyl-pyrimidin-2-yl)-3R-methyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.

¹H NMR (CDCl₃, 400 MHz) δ 8.17 (d, 1H), 6.36 (d, 1H), 6.32 (s, 1H), 4.98(m, 1H), 4.69 (q, 1H), 4.58, (dt, 1H), 4.51 (s, 2H), 4.37-4.11 (c, 3H),3.62 (br s, 1H), 3.48-3.36 (c, 2H), 3.18 (td, 1H), 20.31 (s, 3H), 1.49(d, 3H), 1.17 (s, 3H); MS (APCI) 359 (MH⁺); [α]_(D) −40.6 (c 1.0, MeOH)

Example 69

1R-{4-[4-(4-Hydroxymethyl-6-methyl-pyrimidin-2-yl)3S-methyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.

¹H NMR (CDCl₃, 400 MHz) δ 8.17 (d, 1H), 6.36 (d, 1H), 6.33 (s, 1H), 4.99(m, 1H), 4.69 (q, 1H), 4.58 (m, 1H), 4.52 (s, 2H), 4.40-4.11 (c, 3H),3.60 (br s, 1H), 3.45-3.34 (c, 2H), 3.19 (td, 1H), 2.32 (s, 3H), 1.49(d, 3H), 1.16 (s, 3H); MS (APCI) 359 (MH⁺); [α]_(D) +68.1 (c 0.7, MeOH).

Exam- ple R¹¹ R¹² R⁷ R⁶ mp (° C.) MS (MH⁺) 70 H OH 3R-Me 5S-Me 331 71 MeOH 3R-Me 5S-Me 231-232 345 72 Ph OH 3R-Me 5S-Me 407 73 Me ethoxy- 3R-Me5S-Me 387 methyl 74 Me ethoxy- 2R-Me 6S-Me 106-108 387 methyl

Example 75

(R)-5-[2-(1-Hydroxy-ethyl)-pyrimidin-4-yl]-1-methyl-2-quinoxalin-2-yl-1,2,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one.

Step A:3-Oxo-2-quinoxalin-2-yl-1,2,3,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester. To a solution of4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester(500 mg, 1.84 mmol; Tetrahedron 1994, 50, 515) in toluene (10 mL) wasadded quinoxalin-2-yl-hydrazine (295 mg, 1.85 mmol; Heterocycles 1985,23, 2603). This mixture was stirred at reflux overnight, cooled to roomtemperature, concentrated, and purified by flash column chromatography(2575% ethyl acetate/hexanes) to give 600 mg (89%) of the title compoundof Example 75, Step A as a light orange solid. ¹H NMR (CDCl₃, 250 MHz,5:1 mixture, of tautomers) δ 11.94 (brs, 0.83H), 10.16 (s, 0.17H), 9.57(s, 0.83H), 8.13 (dd, 1H), 7.91-7.69 (c, 3H), 4.45 (s, 1.66H), 4.33 (s,0.34H), 3.79-3.72 (c, 2H), 2.82-2.72 (c, 2H), 1.52 (s, 9H); MS (APCI)368 (MH⁺).

Step B:1-Methyl-3-oxo-2-quinoxalin-2-yl-1,2,3,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester. To a solution of3-oxo-2-quinoxalin-2-yl-1,2,3,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester (prepared according to the method of Example 75,Step A, 250 mg, 0.68 mmol) in dimethylformamide (2 mL) at 0° C. withstirring under nitrogen was added sodium hydride (60% dispersion inmineral oil, 41 mg, 1.02 mmol). After 10 min, iodomethane (51 μL, 0.82mmol) was added. This mixture was allowed to stir at 0° C. for 2 h,quenched by addition of saturated aqueous sodium bicarbonate andextracted with ethyl acetate (4×). The combined organic extracts weredried over sodium sulfate, filtered, evaporated, and purified by flashcolumn chromatography (40% ethyl acetate/hexanes) to give 164 mg (63%)of the title compound of Example 75, Step B as a yellow foam. ¹H NMR(CDCl₃, 250 MHz) δ 9.71 (s, 1H), 8.15 (dd, 1H), 8.02 (m, 1H), 7.80-7.70(c, 2H), 4.29 (s, 2H), 4.14 (t, 2H), 3.79 (s, 3H), 2.72-2.67 (c, 2H),1.50 (s, 9H); MS (APCI) 382 (MH⁺).

Step C:1-Methyl-2-quinoxalin-2-yl-1,2,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-onehydrochloride. To a solution of1-methyl-3-oxo-2-quinoxalin-2-yl-1,2,3,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester (prepared according to the method of Example 75,Step B, 279 mg, 0.73 mmol) in methanol (6 mL) was added hydrogenchloride (5.85 M in methanol, 1.25 mL, 7.3 mmol). This mixture washeated at 60° C. for 30 min, cooled to room temperature, andconcentrated to give 249 mg (>100%) of the title compound of Example 75,Step C as a dark red solid. ¹H NMR (CD₃OD, 250 MHz) δ 9.45 (s, 1H), 8.13(dd, 1H), 8.05 (m, 1H), 7.91-7.83 (c, 2H), 4.05 (s, 2H), 3.64 (t, 2H),3.56 (s, 3H), 3.12 (t, 2H); MS (APCI) 282 (MH⁺).

Step D:(R)-1-[4-(1-Methyl-3-oxo-2-quinoxalin-2-yl-1,2,3,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-pyrimidin-2-yl]-ethylbutyrate. To a stirred solution of1-methyl-2-quinoxalin-2-yl-1,2,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-onehydrochloride (prepared according to the method of Example 75, Step C,175 mg, 0.55 mmol) and (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate(prepared according to the method of Preparation Seven, 126 mg, 0.55mmol) in isopropanol (6 mL) was added triethylamine (230 μL, 1.66 mmol).This mixture was heated to reflux overnight, cooled to room temperature,and evaporated. The residue was diluted, with saturated aqueous sodiumbicarbonate and extracted with chloroform (3×). The combined organicextracts were dried over sodium sulfate, filtered, evaporated, andpurified by flash column chromatography (1.5% methanol/chloroform) togive 248 mg (95%) of the title compound of Example 75, Step D as ayellow oil. ¹H NMR (CDCl₃, 250 MHz) δ 9.70 (s, 1H), 8.29 (d, 1H), 8.15(dd, 1H), 8.03 (m, 1H), 7.82-7.70 (c, 2H), 6.48 (d, 1H) 5.72 (q, 1H),4.36 (s, 2H), 4.35-4.15 (c, 2H), 3.42 (s, 3H), 2.77-2.82 (c, 2H), 2.43(t, 2H), 1.79-1.60 (c, 2H), 1.61 (d, 3H), 0.99 (t, 3H); MS (APCI) 474(MH⁺).

Step E:(R)-5-[2-(1-Hydroxy-ethyl)-pyrimidin-4-yl]-1-methyl-2-quinoxalin-2-yl-1,2,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one.To a solution of(R)-1-[4-(1-methyl-3-oxo-2-quinoxalin-2-yl-1,2,3,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-pyrimidin-2-yl]-ethylbutyrate (prepared according to the method of Example 75, Step D, 248mg, 0.52 mmol) in a 5:2 mixture of methanol/tetrahydrofuran (7 mL) wasadded potassium carbonate (218 mg, 1.57 mmol). This mixture was stirredat room temperature overnight and evaporated. The residue was dilutedwith saturated aqueous sodium bicarbonate and extracted with chloroform(3×). The combined organic extracts were dried over sodium sulfate,filtered, evaporated, and purified by flash column chromatography (1.53%methanol/chloroform) to give 150 mg (71%) of the title compound as awhite solid. mp: 217-219° C. (dec); ¹H NMR (CDCl₃, 250 MHz) δ 9.66 (s,1H), 8.25 (d, 1H), 8.12 (dd, 1H), 7.99 (m, 1H), 7.68-7.78 (c, 2H), 6.47(d, 1H), 4:72 (q, 12H), 4.32 (s, 2H), 4.19-4.14 (c, 3H), 3.41 (s, 3H),2.80 (t, 2H), 1.51 (d, 3H); MS (APCI) 404 (MH⁺); [α]_(D) +13.4 (c 1.5,CHCl₃).

Examples 76 and 77

Examples 76 and 77 were prepared from the appropriate starting materialsin a manner analogous to the method of Example 75.

Example A R³³ B mp (° C.) MS (MH⁺) 76 N—Me benzothiazol-2-yl CO 176-178409 77 CO quinoxalin-2-yl N—Me 201-204 (dec) 404

Example 78

(R)-6-Chloro-1′-[2-(1-hydroxy-ethyl)-pyrimidin4-yl]-spiro[chroman-2.4′-piperidin]-4one.

Step A: 6-Chloro-spiro[chroman-2.4′-piperidin]-4-one hydrochloride. To asolution of 1′-benzyl-6-chloro-spiro[chroman-2,4′-piperidin]4-one (300mg, 0.88 mmol, Chem. Pharm. Bull. 1981, 29, 3494) in acetone (5 mL) at0° C. was added 1-chloroethyl chloroformate (0.29 mL, 2.64 mmol). Thismixture was warmed to room temperature, stirred overnight, andconcentrated. The residue was purified by flash column chromatography(1020% ethyl acetate/hexanes) to give the intermediate carbamate whichwas refluxed in methanol (3 mL) for 1 h. Evaporation of the reactionmixture provided 149 mg (59%) of the title compound of Example 78, StepA as a colorless solid. ¹H NMR (CD₃OD, 250 MHz) 87.77 (d, 1H), 7.58 (dd,1H), 7.15 (d, 1H), 3.33 (buried, 4H), 2.90 (s, 2H), 2.46-2.20 (c, 2H),2.04-1.81 (c, 2H); MS; (APCI) 252, 254 (MH⁺).

Step B:(R)-1′-[2-(1-Butyryloxy-ethyl)-pyrimidin-4-yl]-6-chloro-spiro[chroman-2,4′-piperidin]-4-one.To a solution of 6-chloro-spiro[chroman-2,4′-piperidin]-4-onehydrochloride (prepared according to the method of Example 78, Step A,175 mg, 0.61 mmol) in isopropanol (5 mL) was added(R)-1-(4-chloro-pyrimidin-2-yl)ethyl butyrate (prepared according to themethod of Preparation Seven, 160 mg, 0.70 mmol) followed bytriethylamine (0.29 mL, 2.1 mmol). This mixture was stirred at refluxfor 1.5 h, concentrated, and purified by flash column chromatography (1%methanol/chloroform) to give 270 mg (100%) of the title compound ofExample 78, Step B as a yellow oil. ¹H NMR (CDCl₃, 400 MHz) δ 8.19 (d,1H), 7.83 (d, 1H), 7.44 (dd, 1H), 6.97 (d, 1H), 6.37 (d, 1H), 5.64 (q,1H), 4.18 (app s, 2H), 3.34 (t, 2H), 2.72 (s, 2H), 2.37 (t, 2H), 2.10(d, 2H), 1.71-1.60 (c, 4H), 1.55 (d, 3H), 0.94 (t, 3H); MS (APCI) 444,446 (MH⁺).

Step C:(R)-6-Chloro-1′-[2-(1-hydroxy-ethyl)-pyrimidin-4-yl]-spiro[chroman-2.4′-piperidin]-4-one.A mixture of(R)-1′-[2-(1-butyryloxy-ethyl)-pyrimidin-4-yl]-chloro-spiro[chroman-2,4′-piperidin]4-one(prepared according to the method of Example 78, Step B, 270 mg, 0.61mmol) and lithium hydroxide hydrate (80 mg, 1.83 mmol) in a 3:1:1mixture of tetrahydrofuran/methanol/water (5 mL) was stirred at roomtemperature for 1.5 h. The organic solvents were evaporated and theresidue was extracted with chloroform (4×). The combined organicextracts were dried over sodium sulfate, filtered, evaporated, andpurified by flash column chromatography (ethyl acetate) to give 41 mg(18%) of the title compound as a reddish foam. ¹H NMR (CDCl₃, 300 MHz) δ8.19 (d, 1H), 7.82 (d, 1H), 7.44 (dd, 1H), 6.96 (d, 1H), 6.40 (d, 1H),4.65 (q, 1H), 4.20 (app s, 2H), 3.42-3.32 (c, 2H), 2.73 (s, 2H), 2.14(d, 2H), 1.67 (td, 2H), 1.48 (d, 3H); MS (APCI) 374, 376 (MH⁺); [α]_(D)+12.6 (c 0.5, MeOH).

Examples 79 to 85

Examples 79 to 85 were prepared from the appropriate starting materialsin a manner analogous to the method of Example 78.

Example R³⁶ R³⁷ D mp (° C.) MS (MH⁺) 79 6-Ph H CH₂ 402 80 6-Ph H CHOH418 81 6-Ph H CO 416 82 6-OMe H CO 156.5-157.5 370 83 7-Br H CO 418, 42084 5-Cl 6-Cl CO 408, 410 85 6-OMe 7-OMe CO 400

Example 86

(R)-1-[4-(2-Methyl-4-phenyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl)-pyrimidin-2-yl]ethanol.

Step A:7-Benzyl-2-methyl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one. Asolution of sodium ethoxide in ethanol was prepared by addition ofsodium metal (5.7 g, 247 mmol) to absolute ethanol (141 mL). After thesodium metal had all dissolved, ethyl 1-benzyl-3-oxo-4-piperidinecarboxylate hydrochloride (21 g, 70.5 mmol) was added followed byacetamidine hydrochloride (13.3 g, 141 mmol). This mixture was stirredat reflux for 1 h, cooled to room temperature, and concentrated. Theresidue was dissolved in a minimum amount of water and the pH wasadjusted to about 7 with glacial acetic acid. The resulting yellowprecipitate was filtered, washed with water (3×), air-dried for 2 h,then vacuum-dried overnight to provide 17.1 g (95%) of the titlecompound of Example 86, Step A as a yellow solid. ¹H NMR (CDCl₃ 250 MHz)δ 7.35-7.25 (c, 5H), 3.70 (s, 2H), 3.42 (s, 2H), 2.73-2.64 (c, 2H),2.64-2.60 (c, 2H), 2.41 (s, 3H); MS (APCI) 256 (MH⁺).

Step B:7-Benzyl-4-chloro-2-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine.7-Benzyl-2-methyl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one(prepared according to the method of Example 86, Step A, 17.1 g, 67.0mmol) was suspended in phosphorus oxychloride (66 mL, 335 mmol). Thismixture was stirred at reflux for 1 h, cooled to room temperature,evaporated, then chased with toluene. The residue was carefully dilutedwith ice/water/chloroform and the layers were separated. The aqueousphase was extracted with chloroform (3×) and the combined organicextracts were washed with saturated aqueous sodium bicarbonate (1×) andwater (1×), dried over sodium sulfate, filtered, and evaporated to givethe title compound of Example 86, Step B as a brown oil that was usedwithout purification in the next step. ¹H NMR (CDCl₃, 250 MHz) δ7.36-7.23 (c, 5H), 3.73 (s, 2H), 3.63 (s, 2H), 2.63 (app s, 4H), 2.36(s, 3H); MS (APCI) 274, 276 (MH⁺).

Step C:7-Benzyl-2-methyl-4-phenyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine. To asuspension of 1,4-diphenylphosphinobutane (1.43 g, 3.35 mmol) in toluene(50 mL) was added bis(benzonitrile)palladium(II) chloride (1.28 g, 3.35mmol). This mixture was stirred for 25 min at room temperature, then wasadded to a suspension of 7-,benzyl-4-chloro-2-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine(prepared according to the method of Example 86, Step B, 67.0 mmol,assumed) and phenylboronic acid (10.6 g, 87.1 mmol) in a mixture ofabsolute ethanol (40 mL), toluene (175 mL), and 2 N aqueous sodiumcarbonate (33.5 mL). This mixture was stirred at reflux for 6.5 h,cooled to room temperature and stirred for ˜2.5 d, then filtered througha pad of Celite. The filtrate was concentrated and the residue wasdiluted with water and extracted with chloroform (3×). The combinedorganic extracts were dried over sodium sulfate, filtered, evaporated,and purified by flash column chromatography (45→50% ethylacetate/hexanes) to give 16.5 g (78%, two steps) of the title compoundof Example 86, Step C as a yellow oil. ¹H NMR (CDCl₃, 250 MHz) δ7.57-7.54 (c, 2H), 7.48-7.24 (c, 8H), 3.71 (app s, 4H), 2.85 (t, 2H),2.71-2.67 (c, 2H), 2.69 (s, 3H); MS (APCI) 316 (MH⁺).

Step D: 2-Methyl-4-phenyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine.7-Benzyl-2-methyl-4-phenyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidinehydrochloride was formed in situ by addition of hydrogen chloride (1.9 Min methanol, 31.1 mL, 51.1 mmol) to a solution of7-benzyl-2-methyl-4-phenyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine(prepared according to the method of Example 86, Step C, 16.5 g, 52.2mmol) in methanol (75 mL). After stirring 10 min at room temperature, aprecipitate formed, and another aliquot of methanol (100 mL) was addedto obtain a homogeneous solution. To this mixture was added a slurry of10% palladium on carbon (3.3 g, 20 wt %) in methanol followed ibyammonium formate (16.5 g, 261 mmol). This mixture was stirred at refluxfor 5 h, cooled to room temperature, and filtered through Celite. Thefiltrate was evaporated, diluted with saturated aqueous sodiumbicarbonate, and extracted with chloroform (3×). The combined, organicextracts were dried over sodium sulfate, filtered, evaporated, andpurified by flash column chromatography (3% methanol/chloroform, +1%ammonium hydroxide) to give 6.7 g (57%) of the title compound of Example86, Step D as an off-white solid and 2.4 g (19%) of7-formyl-2-methyl-4-phenyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine as ayellow gum. Treatment of the, 7-formyl byproduct with methanolichydrogen chloride at room temperature overnight followed by aqueousworkup and, column chromatography provided an additional 1.4 g (12%) ofthe title compound of Example 86, Step D. ¹H NMR (CDCl₃, 250 MHz) δ7.55-7.40 (c, 5H), 4.09 (s, 2H) 3.05 (t, 2H), 2.75 (t, 2H), 2.79 (s,3H); MS (APCI) 226 (MH⁺).

Step E:(R)-1-[4-(2-Methyl-4-phenyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl)_(m)pyrimidin-2-yl]-ethyl butyrate. To a solution of2-methyl-4-phenyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine (preparedaccording to the method of Example 86, Step D, 6.8 g, 30.0 mmol) inisopropanol (125 mL) was added (R)-1-(4-chloro-pyrimidin-2-yl)-ethylbutyrate (prepared according to the method of Preparation Seven, 6.8 g,30 mmol) followed by triethylamine (12.5 mL, 89.9 mmol). This mixturewas stirred at reflux for 8 h, cooled to room temperature overnight, andevaporated. The residue was diluted with saturated aqueous sodiumbicarbonate and extracted with ethyl acetate (3×). The combined organicextracts were dried over sodium sulfate, filtered, evaporated, andpurified by flash column chromatography (2% methanol/ethyl acetate) togive 11.0 g (88%) of the title compound of Example 86, Step E, as ayellow oil. ¹H NMR (CDCl₃, 250 MHz) 68.28 (d, 1H), 7.62-7.40 (c, 5H),6.45 (d, 1H), 5.69 (q, 1H), 4.78 (s, 2H), 3.93 (app s, 2H), 2.95 (t,2H), 2.77 (s, 3H), 2.40 (t, 2H), 1.77-1.63 (c, 2H), 1.60 (d, 3H), 0.98(t, 3H); MS (APCI) 418 (MH⁺).

Step F:(R)-1-[4-(2-Methyl-4-phenyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl)-pyrimidin-2-yl]-ethanol.To a solution of(R)-1-[4-(2-methyl-4-phenyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl)-pyrimidin-2-yl]-ethylbutyrate (prepared according to the method of Example 86, Step E, 11.0g, 26.4 mmol) in dioxane (13 mL) was added concentrated hydrochloricacid (22 mL, 264 mmol). This mixture was stirred at room temperatureovernight, cooled to 0° C., neutralized via slow addition of 6 N aqueoussodium hydroxide, and extracted with ethyl acetate (4×). The combinedorganic extracts were dried over sodium sulfate, filtered, evaporated,and purified by flash column chromatography (25% methanol/ethyl acetate)to give an oil which after titration with hexanes provided 8.0 g (88%)of the title compound as a white solid. mp: 114-116° C.; ¹H NMR (CD₃OD,250 MHz) 68.26 (d, 1H), 7.62-7.47 (c, 5H), 6.52 (d, 1H), 4.79 (s, 2H),4.66 (q, 1H), 4.24 (br s, 1H), 3.90-3.80 (c, 2H), 2.95 (t, 2H), 2.70 (s,3H), 1.49 (d, 3H); MS (APCI) 348 (MH⁺), [α]_(D) +15.6 (c 1.0, MeOH).

Examples 87 to 100

Examples 87 to 100 were prepared from the appropriate starting materialsin a analogous to the method of Example 86.

Example R²⁹ R²⁸ mp (° C.) MS (MH⁺) 87 H Ph 72-74 334 88 Ph H 334 89 PhEt 362 90 Ph NH₂ 225-228 (dec) 349 91 Ph Ph  73-75 410 92 Ph 4-pyridyl411 93 (4-OMe)Ph Me  62-64 378 94 (4-F)Ph Me  55-58 366 95 (4-Cl)Ph H368, 370 96 OMe Me 302 97 OPh Me 156-158 364 98 SPh Me 103-105 380 99N-indolinyl Me 128-131 389 100 NMe₂ Et 329

Example 101

{4-[2-(1R-Hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-(2-phenyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)-methanone.

Step A: 4-Oxo-piperidine-1-carboxylic acid tert-butyl ester. A mixtureof 4-piperidone monohydrate hydrochloride (9.22 g, 60 mmol) anddi-tert-butyl dicarbonate (10.9 g, 50 mmol) in a 1:1 mixture ofdichloromethane/saturated aqueous sodium bicarbonate (100 mL) wasstirred at room temperature for 15.5 h. The layers were separated andthe aqueous layer was extracted with chloroform (3×). The combinedorganic extracts were washed with 1 N aqueous phosphoric acid (3×),dried over sodium sulfate, filtered, and evaporated to give 10.0 g(100%) of the title compound of Example 101, Step A as a white solid. ¹HNMR (CDCl₃, 400 MHz) δ 3.70 (t, 4H), 2.42 (t, 4H), 1.47 (5, 9H).

Step B: 3-Dimethylaminomethylene-4-oxo-piperidine-1-carboxylic acidtert-butyl ester. To a solution of 4-oxo-piperidine-1-carboxylic acidtert-butyl ester (prepared according to the method of Example 101, StepA, 4.0 g, 20.0 mmol) in dimethylformamide (40 mL) was addedtert-butoxybis(dimethylamino)methane (4.35 mL, 22 mmol). This mixturewas stirred at reflux for 15 h, cooled to room temperature, diluted withwater, and extracted with ethyl acetate (5×). The combined organicextracts were washed with water (3×) and brine (1×), dried over sodiumsulfate, filtered, and evaporated to give 3.64 g (72%) of the titlecompound of Example 101, Step B as a brown oil that was sufficientlypure to carry on to the next step. ¹H NMR (CDCl₃, 400 MHz) δ 7.47 (s,1H), 4.53 (s, 2H), 3.58 (t, 2H), 3.09 (s, 6H), 2.43 (t, 2H), 1.46 (s,9H); MS (APCI) 255 (MH⁺).

Step C: 2-phenyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylicacid tert-butyl ester. A mixture of3-dimethylaminomethylene-4-oxo-piperidine-1-carboxylic acid tert-butylester (prepared according to the method of Example 101, Step B, 509 mg,2.0 mmol), benzamidine hydrochloride hydrate (470 mg, 3.0 mmol), andsodium, ethoxide (1 M in ethanol, 6.0 mL, 6.0 mmol) in absolute ethanol(4 mL) was heated to reflux for about 3 d, cooled to room temperature,and concentrated. The residue was diluted with saturated aqueous sodiumbicarbonate and extracted with chloroform (3×). The combined organicextracts were dried over sodium sulfate, filtered, evaporated, andpurified by flash column chromatography (Biotagq Flash 40S™, 10→15%ethyl acetate/hexanes) to give 304 mg (49%) of the title compound ofExample 101, Step C as a yellow oil. ¹H NMR (CDCl₃, 400 MHz) δ 8.52 (s,1H), 8.40-8.38 (c, 2H), 7.50-7.44 (c, 3H), 4.62 (s, 2H), 3.78 (t, 2H)3.02 (t, 2H), 1.50 (s, 9H); MS (APCI) 312 (MH⁺).

Step D: 2-phenyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine hydrochloride.To a solution of2-phenyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acidtert-butyl ester (prepared according to the method of Example 101, StepC, 304 mg, 0.98 mmol) in ethyl acetate (2 mL) was added hydrogenchloride (2.5 M in ethyl acetate, 3.9 mL, 9.76 mmol). This mixture wasstirred at room temperature for 16 h and concentrated to give 256 mg(>100%) of the title compound of Example 101, Step D as a pale yellowsolid. ¹H NMR (CD₃OD, 400 MHz) δ 8.75 (s, 1H), 8.42-8.38 (c, 2H),7.51-7.45 (c, 3H), 4.48 (s, 2H), 3.68 (t, 2H) 3.35-3.25 (buried, 2H); MS(APCI) 212 (MH⁺).

Step E:1R-[4-(4-Chlorocarbonyl-3R,5S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethylbutyrate. To a solution of1R-[4-(3R,5S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl butyrate(prepared according to the method of Preparation Three, 1.36 g, 4.44mmol) in dichloromethane (22 mL) at 0° C. under nitrogen was addedpyridine (0.36 mL, 4.44 mmol) followed by triphosgene (883 mg, 2.97mmol). This mixture was stirred with warming to room temperature for 1.5h and quenched with saturated aqueous sodium bicarbonate. The layerswere separated and the aqueous phase was extracted with chloroform (3×).The combined organic extracts were dried over sodium sulfate, filtered,evaporated, and purified by flash column chromatography (1→2%methanol/chloroform) to give 1.59 g (97%) of the title compound ofExample 101, Step E as a brown oil. ¹H NMR (CDCl₃, 400 MHz) δ 8.23 (d,1H), 6.39(d, 1H), 5.66 (q, 1H), 4.54-4.47 (c, 2H), 4.35 (m, 1H), 4.25(m, 1H), 3.20 (dt, 2H), 2.38 (t, 2H), 1.72-1.62 (c, 2H), 1.56 (d, 3H),1.31 (d, 3H), 1.30 (d, 3H), 0.95 (t, 3H); MS (APCI) 369, 371 (MH⁺).

Step F:{4-[2-(1R-Hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-(2-phenyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)-methanone.A mixture of 2-phenyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidinehydrochloride (prepared according to the method of Example 101, Step D,160 mg, 0.65 mmol),1R-[4-(4-chlorocarbonyl-3R,5S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethylbutyrate (prepared according to the method of Example 101, Step E, 200mg, 0.54 mmol), and triethylamine (0.19, mL, 1.36 mmol) intetrahydrofuran (5 mL) was stirred at reflux for 3 h, cooled to roomtemperature overnight, and concentrated. The residue was diluted with a4:1 mixture of methanol/water (5 mL) and lithium hydroxide hydrate (114mg, 2.71 mmol) was added. This mixture was stirred for 2.5 h,concentrated, and partitioned between saturated aqueous sodiumbicarbonate and chloroform. The layers were separated and the aqueousphase was extracted with 20% isopropanol/chloroform (3×). The combinedorganic extracts were dried over sodium sulfate, filtered, evaporated,and purified by flash column chromatography (2→5% methanol/chloroform)to give 183 mg (71%) the title compound as a white foam. ¹H NMR (CDCl₃,400 MHz) δ 8.56 (s, 1H), 8.41-8.39 (c, 2H), 8.20 (d, 1H), 7.50-7.46 (c,3H), 6.38 (d, 1H), 4.71 (s, 2H), 4.69 (m, 1H), 4.28 (d, 1H), 3.89 (t,2H) 3.83 (d, 2H), 3.60-3.56 (c, 2H), 3.46-3.39 (c, 2H), 3.09 (t, 2H),1.50 (d, 3H), 1.18 (d, 6H); MS (APCI) 212 (MH⁺); [α]D+6.1 (c 1.8,CHCl₃).

Examples 102 to 110

Examples 102 to 110 were prepared from the appropriate startingmaterials in a manner analogous to the method of Example 101.

Example R²² R²¹ R¹⁸ R¹⁹ mp (° C.) MS (MH⁺) 102 quinolin-2-yl H 3R-Me5S-Me 172-174.5 407 103 quinolin-3-yl H 2R-Me 6S-Me 407 104quinolin-4-yl H 3R-Me 5S-Me 407 105 quinolin-6-yl H 3R-Me 5S-Me 407 106pyqidin-3-yl- pyridin-3- 2R-Me 6S-Me 462 methyl methyl Example NR²¹R²²R¹⁸ R¹⁹ mp (° C.) MS (MH⁺) 107 2-amino-7,8-dihydro-5H- 2R-Me 6S-Me225-228 413 pyrido[4,3-d]pyrimidin-6-yl 108 2-(1-hydroxy-1-methyl- 2R-Me6S-Me 456 ethyl)-7,8-dihydro-5H- pyrido[4,3-d]pyrimidin-6-yl 1095,7-dihydro- 2R-Me 6S-Me 458 dibenzo[c,e]azepin-6-yl 1104-[2-(1R-hydroxy-ethyl)- 3R-Me 5S-Me 499 pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl

Example 111

4-[4-(2-phenyl-ethenesulfonyl)-piperazin-1-yl]-pyrimidin-2-yl)-ethanol.

Step A:(E)-1R-{4-[4-(2-phenyl-ethenesulfonyl)-piperazin-1-yl]-pyrimidin-2-yl}-ethylacetate. To a solution of (R)-1-[4-piperazin-1-yl)-pyrimidin-2-yl]-ethylacetate (prepared according to the method of Preparation Two, 0.25 g,1.0 mmol) and triethylamine (0.10 g, 1.0 mmol) in tetrahydrofuran (5 mL)was added β-styrenesulfonyl chloride (0.21 g, 1.0 mmol) at ambienttemperature and stirred for 1 h. The mixture was diluted with water andextracted twice with ethyl acetate. The extract was dried over magnesiumsulfate, filtered, and the filtrate was concentrated to an oil, whichwas purified by flash chromatography (9:1 dichloromethane:methanol) togive the title compound of Example 111, Step A as an oil, 0.15 g (34%).¹H NMR (CDCl₃, 300 MHz) δ 1.48 (d, 3H), 2.15 (s, 3H), 3.23 (m, 4H), 3.84(m, 4H), 5.61 (q, 1H), 6.40 (d, 1H), 6.65 (d, 1H), 7.39-7.52 (m, 6H),8.21 (d, 1H); MS (TS) 417 (MH⁺).

Step B:(E)-1R-{4-[4-(2-phenyl-ethenesulfonyl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.

To a solution(E)-1R-{4-[4-(2-phenyl-ethenesulfonyl)-piperazin-1-yl]-pyrimidin-2-yl}-ethylacetate (prepared according the method of Example 111, Step A, 0.14 g,0.33 mmol) in methanol (1 mL) was added at ambient temperature 6 Naqueous potassium hydroxide (0.25 mL). After stirring for 3 h, thesolution was diluted with ethyl acetate and washed twice with water. Theorganic layer was separated, dried over magnesium sulfate, filtered, andthe filtrate was concentrated to give the title compound as a whitesolid, 0.09 g (69%). ¹H NMR (CDCl₃, 300 MHz) 6.1.48 (d, 3H), 3.23 (m,4H), 3.84 (m, 4H), 4.20 (br s, 1H), 4.71 (q, 1H), 6.40 (d, 1H), 6.65 (d,1H), 7.39-7.52 (m, 6H), 8.21 (d, 1H); mp: 68-70° C.; MS (TS) 375 (MH⁺);[α]_(D) +20.9 (c 1.0, MeOH).

Examples 112 and 113

Examples 112 and 113 were prepared from the appropriate startingmaterials in a manner analogous to the method of Example 111.

Example R¹⁸ R¹⁹ R¹⁷ mp (° C.) MS (MH⁺) 112 (R)-Me (S)-Meisopropylsulfonyl 152-154 343 113 (R)-Me (S)-Me 1-methyl-1H-imidazol-4-157-158 381 yl-sulfonyl

Example 114

1R-{4-[5-(4-Bromobenzenesulfonyl)-2R,5S-diaza-bicyclo[2.2.1]hept-2-yl]-pyrimidin-2-yl}-ethanol.

Step A:1R-[4-(2R,5S-Diaza-bicyclo[2.2.1]hept-2-yl)-pyrimidin-2-yl]-ethylbutyrate. To a suspension of 2,5-diaza-bicyclo[2.2.1]heptanedihydrobromide (7.57 g, 88.0 mmol; Synthesis 1990, 10, 925) indichloromethane (90 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene(13.7 g, 90 mmol) and stirred until homogeneous. A solution of(R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according tothe method of Preparation Seven, 10.2 g, 45 mmol) in dichloromethane (10mL) was added and stirred at reflux for 14 h. The mixture was filteredand washed with saturated aqueous sodium bicarbonate. The organic layerwas dried over sodium sulfate and filtered. The filtrate wasconcentrated to obtain a crude product which was purified by flashchromatography (9:1→5:1 dichloromethane:methanol) to give the titlecompound of Example 114, Step A as an oil, 6.75 g (51%). ¹H NMR (CDCl₃,300 MHz) δ 0.92 (t, 3H), 1.54 (d, 3H), 1.68-1.78 (m, 5H), 2.68 (t, 2H),3.38 (m, 1H), 3.76 (m, 3H), 4.42 (m, 1H), 5.35 (q, 1H), 6.16 (d, 1H),8.12 (d, 1H); MS (CI) 291

Step B:1R-{4-[5-(4-Bromobenzenesulfonyl)-2R,5S-diaza-bicyclo[2.2.1]hept-2-yl]-pyrimidin-2-yl}-ethylbutyrate. To a solution of1R-[4-(2R,5S-diaza-bicyclo[2.2.1]hept-2-yl)-pyrimidin-2-yl]-ethylbutyrate (prepared according to the method of Example 114, Step A, 0.58g, 2.0 mmol) and triethylamine (0.22 g, 2.2 mmol) in chloroform (10 mL)was added 4-bromobenzenesulfonyl chloride (0.56 g, 2.2 mmol) and stirredat ambient temperature for 16 h. The mixture was washed once with water,once with brine, dried over magnesium sulfate, filtered, and thefiltrate was concentrated to give the title compound of Example 114,Step B as a clear oil, 0.92 g (90%). ¹H NMR (CDCl₃, 300 MHz) δ 0.92 (t,3H), 1.54 (d, 3H), 1.68-1.78 (m, 5H), 2.68 (t, 2H), 3.25 (m, 1H), 3.46(m, 3H), 4.28 (m, 1H), 5.25 (q, 1H), 6.16 (d, 1H), 7.58-7.64 (m, 4H),8.12 (d, 1H); MS (CI) 510 (MH⁺).

Step C:1R-{4-[5-(4-Bromobenzenesulfonyl)-2R,5S-diaza-bicylo[2.2.1]hept-2-yl]-pyrimidin-2-yl}-ethanol.To a solution of1R-{4-[5-(4-bromobenzenesulfonyl)-2R,5S-diaza-bicyclo[2.2.1]hept-2-yl]-pyrimidin-2-yl}-ethylbutyrate (prepared according to the method of Example 114, Step B, 0.85g 1.6 mmol) in a 2:1 mixture of tetrahydrofuran:methanol (10 mL) wasadded at ambient temperature 6 N aqueous potassium hydroxide (1 mL).After stirring for 6 h the solution was diluted with dichloromethane andwashed twice with water. The organic layer was separated, dried overmagnesium sulfate, filtered, and the filtrate was concentrated to aviscous oil which was purified by flash chromatography (9:1dichloromethane:methanol) to give the title compound as a white foam,0.49 g (66%). ¹H NMR (CDCl₃, 300 MHz) δ 1.54 (d, 3H), 1.68 (m, 2H), 1.78(m, 1H), 3.25 (m, 1H), 3.46 (m, 3H), 4.28 (m, 1H), 4.78 (q, 1H), 6.16(d, 1H), 7.64 (m, 4H), 8.12 (d, 1H); mp: 83-88° C.; MS (CI) 440 (MH⁺);[α]_(D) +49.2 (c 1.0, MeOH).

Examples 115 to 120

Examples 115 to 120 were prepared from the appropriate startingmaterials in a manner analogous to the method of Example 114.

Example R¹⁷ mp (° C.) MS (MH⁺) 115 4-chlorophenylsulfonyl 83-88 395, 397116 2-thienylsulfonyl 84-86 367 117 2-(5-chlorothienyl)-sulfonyl 62-64401, 403 118 4-carboxamidoylphenyl-sulfonyl 148-151 404 1194-(tert-butylphenyl)-sulfonyl 72-75 417 120 N,N-dimethylsulfamoyl110-111 328

Example 121

{4-[4-(Pyrrolidine-1-sulfonyl)-piperazin-1-yl]-pyrimidin-2-yl}-methanol.

Step A:2-Methoxymethyl-4-[4-(pyrrolidine-1-sulfonyl)-piperazin-1-yl]-pyrimidine.To a solution of 2-methoxymethyl-4-piperazin-1-yl-pyrimidine (preparedaccording to the method of Preparation One, 2.08 g, 10 mmol) andtriethylamine (1.01 g, 10 mmol) in tetrahydrofuran (20 mL) was addedN-pyrrolidinesulfonyl chloride (1.69 g, 10 mmol) at 0° C. and stirredfor 3 h at ambient temperature. The mixture was diluted with ethylacetate and washed twice with water. The organic layer was separated,dried over magnesium sulfate, filtered, and the filtrate wasconcentrated to an oil which was purified by flash chromatography (95:5dichloromethane:methanol) to give the title compound of Example 121,Step A as a clear oil, 3.24 g (93%). ¹H NMR (CDCl₃, 300 MHz) δ 1.81-1.85(m, 4H), 3.12-3.18 (m, 8H), 3.59 (s, 3H), 3.81 (m, 4H), 4.43 (s, 2H),6.71 (d, 1H), 8.18 (d, 1H); MS (TS) 342 (MH⁺).

Step B:{4-[4-(pyrrolidine-1-sulfonyl)-piperazin-1-yl]-pyrimidin-2-yl}-methanol.To a solution of2-methoxymethyl-4-[4-(pyrrolidine-1-sulfonyl)-piperazin-1-yl]-pyrimidine(prepared according to the method of Example 121, Step A, 3.1 g, 9.4mmol) in dichloromethane (47 mL) was added boron tribromide (1, M indichloromethane, 19 mL, 18.7 mmol) at 0° C. then stirred at ambienttemperature for 2 h. The mixture was washed twice with saturated aqueoussodium bicarbonate, and the organic layer was separated, dried overmagnesium sulfate, filtered, and the filtrate was concentrated to givean oil which was crystallized from isopropyl ether to give the titlecompound as a white solid, 2.431 g (77%). ¹H NMR (CDCl₃, 300 MHz) δ 1.82(m, 4H), 3.15 (m, 8H), 3.81 (m, 4H), 4.35 (d, 2H), 4.83 (t, 1H), 6.71(d, 1H), 8.18 (d, 1H); mp: 128-131° C.; MS (CI) 328 (MH⁺).

Examples 122 to 125

Examples 122 to 125 were prepared from the appropriate startingmaterials in a manner analogous to, the method of Example 121.

Ex- am- mp ple R¹ R¹⁷ (° C.) MS (MH⁺) 122 CH₂OH2,5-dimethylpyrrolidin-1- 128- 356 ylsulfonyl 131 123 CH₂OHpiperidin-1-ylsulfonyl 141- 342 142 124 (R)-CH(Me)OHaza-bicyclo[3.2.1]octan-8- 111- 382 ylsulfonyl 112 125 (R)-CH(Me)OHaza-bicyclo[3.2.1]octan-3- 113- 396 one-8-yl-sulfonyl 114

Example 126

(E)-1-{4-[2-(1R-Hydroxy-ethyl)-pyrimidin-4-yl]-piperazin-1-yl}-2-methyl-3-phenyl-propenone.

Step A:(E)-1R-{4-[4-(2-Methyl-3-phenyl-acryloyl)-piperazin-1-yl]-pyrimidin-2-yl}-ethylacetate. To a solution of (R)-1-(4-piperazin-1-yl-pyrimidin-2-yl)-ethylacetate (prepared according to the method of Preparation Two, 0.54 g,2.1 mmol) and α-methylcinnamic acid (0.34 g, 2.1 mmol) indichloromethane (10 mL) was added 1-hydroxybenzotriazole (0.50 g, 3.6mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (0.45 g, 2.4 mmol) at ambient temperature and stirred for48 h. The mixture was washed once with water, once with saturatedaqueous sodium chloride, dried over magnesium sulfate, filtered, and thefiltrate was concentrated to an oil which was purified by flashchromatography (9:1 dichloromethane:methanol) to give the title compoundof Example 126, Step A as a clear viscous oil, 0.53 g (63%). ¹H NMR(CDCl₃, 300 MHz) δ 1.51 (d, 3H), 2.14 (s, 3H), 2.18 (s, 3H), 3.75 (m,8H), 5.68 (q, 1H), 6.41 (d, 1H), 6.59 (s, 1H), 7.25-7.43 (m, 5H), 8.23(d, 1H); MS (CI) 395 (MH⁺); [α]_(D) +38.6 (c 1.0, MeOH).

Step B:(E)-1-{4-[2-(1R-Hydroxy-ethyl)-pyrimidin-4-yl]-piperazin-1-yl}-2-methyl-3-phenyl-propenone.To a solution of(E)-1R-{4-[4-(2-methyl-3-phenyl-acryloyl)piperazin-1-yl]-pyrimidin-2-yl}-ethylacetate (prepared according to the method of Example 126, Step A, 0.51g, 1.3 mmol) in methanol (5 mL) was added at ambient temperature 6 Naqueous potassium hydroxide (1 mL). After stirring for 1 h the solutionwas diluted with ethyl acetate and washed twice with water. The organiclayer was separated, dried over magnesium sulfate, filtered, and thefiltrate was concentrated to give the title compound as a white solid,0.25 g (55%). ¹H NMR (CDCl₃, 300 MHz) δ 1.51 (d, 3H), 2.14 (s, 3H), 3.75(m, 8H), 4.22 (br s, 1H), 4.71 (q, 1H), 6.41 (d, 1H), 6.59 (s, 1H),7.25-7.43 (m, 5H), 8.23 (d, 1H); mp: 119-121° C.; MS (CI) 353 (MH⁺);[α]_(D) +16.0 (c 1.0, MeOH).

Examples 127 to 129

Examples 127 to 129 were prepared from thee appropriate startingmaterials in a manner analogous to the method of Example 126.

Example Ar¹ R⁶ R⁷ mp (° C.) MS (MH⁺) 127 thien-2-yl H H 104-106 345 128thien-2-yl (R)-Me (S)-Me 69-73 373

Example Ar² mp (° C.) MS (MH⁺) 129 4-(o-tolylcarbamoyl)-phenyl 98-103446

Example 130

(E)-3-Benzofuran-2-yl-1-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-propenone.

Step A:(E)-1R-{4-[4-(3-Benzofuran-2-yl-acryloyl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethylbutyrate. To a solution of1R-[4-(3R,5S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl butyrate(prepared according to the method of Preparation Three, 0.79 g, 2.6mmol) and triethylamine (0.26 g, 2.6 mmol) in dichloromethane (90 mL)was added (E)-3-benzofuran-2-yl-acryloyl chloride (0.54 g, 2.6 mmol) andstirred at ambient temperature for 16 h, then at reflux for 2.5 h. Themixture was washed successively with saturated aqueous sodiumbicarbonate and water, and the organic layer was dried over sodiumsulfate and filtered. The filtrate was concentrated to obtain a crudeproduct, which was purified by flash chromatography (9:1dichloromethane:methanol) to give the title compound of Example 130,Step A as a viscous oil, 0.79 g (54%). ¹H NMR (CDCl₃, 300 MHz) δ 0.95(t, 3H), 1.40 (d, 6H), 1.56 (d, 3H), 1.67 (q, 2H), 2.38 (t, 2H), 3.25(d, 2H), 4.33 (m, 2H), 4.75 (m, 2H), 5.66 (q, 1H), 5.95 (d, 1H), 6.40(d, 1H), 7.14-7.37, (m, 5H), 8.06 (d, 1H), 8.22 (d, 1H); MS (CI) 477(MH⁺); [α]_(D) +49.1 (c 1.0, MeOH).

Step B:(E)-3-Benzofuran-2-yl-1-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-propenone.To a solution of(E)-1R-{4-[4-(3-benzofuran-2-yl-acryloyl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethylbutyrate (prepared according to the method of Example 130, Step A, 0.51g, 1.1 mmol) in methanol (5 mL) was added at ambient temperature 6 Naqueous potassium hydroxide (1 mL). After stirring for 1 h the solutionwas diluted with ethyl acetate and washed twice with water. The organiclayer was separated, dried over magnesium sulfate, filtered, and thefiltrate was concentrated to give the title compound as a white solid,0.49 g (75%). ¹H NMR (CDCl₃, 300 MHz) δ 1.40 (d, 6H), 1.56 (d, 3H), 3.25(d, 2H), 4.33 (m, 2H), 4.75 (m, 2H), 4.68 (q, 1H), 5.95 (d, 1H), 6.40(d, 1H), 7.14-7.37, (m, 5H), 8.06 (d, 1H), 8.22 (d, 1H); mp: 80-82° C.;MS (CI) 407 (MH⁺); [α]_(D) +17.7 (c1.0, MeOH).

Example 131

Cyclohexyl-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-methanone.

Step A:1R-[4-(4-Cyclohexanecarbonyl-3R,5S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethylbutyrate. To a solution of1R-[4-(3R,5S-dimethyl-piperazin-1-yl)-pyrimidin-2-+yl]-ethyl butyrate(prepared according to the method of Preparation Three, 306 mg, 1.0mmol) and triethylamine (230 mg, 1.2 mmol) in dichloromethane (10 mL)was added at ambient temperature cyclohexanecarbonyl chloride (161 mg,1.1 mmol). After 1 h the mixture was washed with water, and thedichloromethane layer was dried over magnesium sulfate and filtered. Thefiltrate was concentrated to give the title compound of Example 131,Step A as an oil, 388 mg (94%). ¹H NMR (CDCl₃, 300 MHz) δ 0.94 (t, 3H),1.2-1.4 (m, 6H), 1.54 (d, 3H), 1.5-1.83 (m, 12H), 2.44 (m, 3H), 3.2-3.3(m, 2H), 4.4-4.6 (m, 4H), 5.52 (q, 1H), 6.44 (d, 1H), 8.22 (d, 1H); MS(CI) 417 (MH⁺).

Step B:Cyclohexyl-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-methanone.To a solution of1R-[4-(4-cyclohexanecarbonyl-3R,5S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethylbutyrate (prepared according to the method of Example 131, Step A, 375mg, 9.0 mmol) in methanol (5 mL) was added 6 N aqueous potassiumhydroxide (0.5 mL) and stirred at ambient temperature for 4 h. Thereaction mixture was concentrated, diluted with water, and extractedinto dichloromethane. The extract was washed twice with water, driedover magnesium sulfate, and evaporated to an oil. The crude product wascrystallized from ethyl ether to give the title compound as a whitesolid, 106 mg (34%). ¹H NMR(CDCl₃, 300 MHz) δ 1.2-1.4 (m, 6H), 1.55 (d,3H), 1.6-1.8 (m, 10H), 2.46 (m, 1H), 3.2-3.3 (m, 2H), 4.2-4.6 (m, 4H),4.78 (q, 1H), 6.43 (d, 1H), 8.22 (d, 1H); mp: 174-175° C.; MS (CI) 347(MH⁺); [α]_(D) +18.4 (c 1.0, MeOH).

Example 132

Furo[3,2-c]pyridin-2-yl-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-methanone.

Step A: 7-Chloro-furo[3,2-c]pyridine-2-carboxylic acid. To a solution ofn-butyllithium (2.5 M in hexanes, 17 mL, g, 42.6 mmol) in anhydrousethyl ether (90 mL) was added dropwise a solution of4-chloro-furo[3,2-c]pyridine (5.81 g, 37.8 mmol; J. Heterocycl. Chem.1975, 12, 705) in ethyl ether (85 mL) at −78° C. under nitrogenatmosphere. This mixture was stirred for 1.5 h at −65° C., poured ontodry ice (100 cc) and warmed to ambient temperature and quenched intowater. The separated organic layer was extracted once with water and thecombined aqueous layers were acidified to pH 2 with concentratedhydrochloric acid to give the title compound of Example 132, Step A as awhite solid, 3.33 g (45%). ¹H NMR (CDCl₃, 300 MHz)δ 7.69 (s, 1H), 7.85(d, 1H), 8.42 (d, 1H); mp: 233-235° C. (dec); MS (CI) 153 (MH⁴—CO₂).

Step B: 7-Chloro-furo[3,2-c]pyridine-2-carboxylic acid chloride.7-Chloro-furo[3,2-c]pyridine-2-carboxylic acid (prepared according tothe method of Example 132, Step A, 8.94 g, 45.2 mmol) was combined withthionyl chloride (30 mL) and sodium carbonate (9.59 g, 90.5 mmol) andheated to reflux for 16 h under nitrogen atmosphere. The cooled mixturewas diluted with dichloromethane and filtered. The filtrate wasevaporated to give the title compound of Example 132, Step B as anorange oil, 9.19 g (94%). The acid chloride was used directly withoutfurther purification.

Step C:1R-{4-[4-(4-Chloro-furo[3,2-c]pyridine-2-carbonyl)-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl-ethylbutyrate. To a solution of1R-[4-(3R,5S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl butyrate(prepared according to the method of Preparation Three, 13.04 g, 42.5mmol) and triethylamine (8.61 g, 85.1 mmol) in dichloromethane (90 mL)was added 7-chloro-furo[3,2-c]pyridine-2-carboxylic acid chloride(prepared according to the method of Example 132, Step B, 9.1 g, 84.0mmol) and stirred at ambient temperature for 2 h. The mixture was washedsuccessively with saturated aqueous sodium bicarbonate and water, andthe organic layer was dried over sodium sulfate and filtered. Thefiltrate was concentrated to obtain a crude product which was purifiedby flash chromatography (9:1 dichloromethane methanol) to give the titlecompound of Example 132, Step C as a viscous oil, 18.9 g (91%). ¹H NMR(CDCl₃, 300 MHz) δ0.95, (t, 3H), 1.40 (d, 6H), 1.56 (d, 3H), 1.67 (m,2H), 2.38 (t, 2H), 3.25 (d, 2H), 4.33 (m, 2H), 4.75 (m, 2H), 5.66 (q,1H), 6.40 (d, 1H), 7.33 (s, 1H), 7.41 (d, 1H), 8.23 (d, 1H), 8.35 (d,1H); MS (CI) 487 (MH⁺); [α]_(D) +33.3 (c 1.0, MeOH).

Step D: 1 If4-(Furo[3,2-c]pyridine-2-carbonyl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl-ethylbutyrate. To a solution of1R-{4-[4-(4-chloro-furo[3,2-c]pyridine-2-carbonyl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethylbutyrate (prepared according to the method of Example 132, Step C, 18.6g, 38.4 mmol) in ethanol (160′ mL) was added, sodium carbonate (4.07 g,38.4 mmol) and 10% palladium on carbon (6.10 g, 33 wt %). This mixturewas hydrogenated at 50 psi hydrogen for 6 h using a Parr apparatus. Thecatalyst was filtered and the filtrate was evaporated to an oil whichwas purified by flash chromatography (9:1 dichloromethane:methanol) togive the title compound of Example 132, Step D as a yellow oil, 14.2 g(82%). ¹H NMR (CDCl₃, 300 MHz) δ 0.95 (t, 3H), 1.40 (d, 6H), 1.56 (d,3H), 1.67 (q, 2H), 2.38 (t, 2H), 3.25 (d, 2H), 4.33 (m, 2H), 4.75 (m,2H), 5.68 (q, 1H), 6.40 (d, 1H), 7.37 (s, 1H), 7.48 (d, 1H), 8.22 (d,1H), 9.04 (s, 1H); MS (CI) 452 (MH⁺); [α]_(D) +36.7 (c 1.0, MeOH).

Step E:Furo[3,2-c]pyridin-2-yl-{4-[2(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-methanone.1R-{4-[4-(Furo[3,2-c]pyridine-2-carbonyl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethylbutyrate (prepared according to the method of Example 132, Step D, 5.48g, 12.1 mmol) was combined with concentrated hydrochloric acid (15 mL)and stirred at ambient temperature for 6 h. The mixture was poured intocold 6 M aqueous sodium hydroxide and extracted twice with ethylacetate. The organic extract was washed once with water, dried oversodium sulfate and evaporated to a foam which crystallized fromisopropyl ether to give the title compound as a white solid, 3.33 g(72%). ¹H NMR (CDCl₃, 300 MHz) δ 1.43 (d, 6H), 1.52 (d, 3H), 3.37 (m,2H), 4.38 (m, 2H), 4.71 (q, 1H), 4.83 (m, 2H), 6.43 (d, 1H), 7.38 (s,1H), 7.47 (m, 1H), 8.22 (m, 1H), 8.54 (d, 1H), 8.58 (d, 1H), 9.04 (s,1H); mp: 142-143° C.; MS (CI) 382 (MH⁺); [α]_(D) +15.9 (c 1.0, MeOH).

Example 133

{4-[2-(1R-Hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-(4-pyrrolidin-1-yl-furo[3,2-c]pyridin-2-yl)-methanone.

A solution of1R-{4-[4-(4-chloro-furo[3,2-c]pyridine-2-carbonyl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethylbutyrate (prepared according to the method of Example 132, Step C, 0.046g, 0.11 mmol) in pyrrolidine (0.037 mL, 0.44 mmol) was heated to refluxfor 14 h and evaporated to give the title compound as a tan solid, 0.04g (80%). ¹H NMR (CDCl₃, 300 MHz) δ 1.43 (d, 6H), 1.53 (d, 3H), 2.08 (m,4H), 3.43 (m, 2H), 3.77 (m, 4H), 4.43 (m, 2H), 4.71 (q, 1H), 4.92 (m,2H), 6.43 (d, 1H), 6.70 (d, 1H), 7.60 (s, 1H), 8.08 (d, 1H), 8.23 (d,1H); MS (CI) 451 (MH⁺).

Examples 134 to 158

Examples 140 and 142 to 158 were prepared from the appropriate startingmaterials in a manner analogous to the method of Example 131. Example141 was prepared from the appropriate starting materials in a manneranalogous to the method of Example 133.

Ex- ample R¹⁷ R¹⁸ R¹⁹ mp (° C.) MS (MH⁺) 134 cyclopropylcarbonyl 2R-Me6S-Me 110-111 305 135 cyclobutylcarbonyl 2R-Me 6S-Me 134-135 319 136cyclopentylcarbonyl 2R-Me 6S-Me 199-200 333 137 tert-butylcarbonyl 2R-Me6S-Me 168-169 321

Ex- am- mp MS ple Ar² R¹⁸ R¹⁹ (° C.) (MH⁺) 138 benzofuran-2-yl 2R-Me6S-Me 124- 381 126 139 furo[3,2-c]pyridin-2-yl H H 55- 354 65 140furo[3,2-c]pyridin-2-yl 3R-Me 5S-Me 382 141 morpholin-4-yl-furo[3,2-2R-Me 6S-Me 467 c]pyridin-2-yl 142 furo[2,3-c]pyridine-2-yl 2R-Me 6S-Me129- 382 131 143 5-chlorobenzofuran-2-yl H H 387, 389 1445-chlorobenzofuran-2-yl 3R-Me 5S-Me 114- 415, 116 417 1455,7-dichlorobenzofuran-2-yl 2R-Me 6S-Me 136- 450, 137 452 1465,7-dichlorobenzofuran-2-yl 3R-Me 5S-Me 152- 450, 153 452 1475-nitrobenzofuran-2-yl 2R-Me 6S-Me 153- 426 154 1485,7-dimethylbenzofuran-2-yl 3R-Me 5S-Me 134- 409 136 1495-methoxybenzofuran-2-yl 3R-Me 5S-Me 137- 411 138 1505-methoxybenzofuran-2-yl 2R-Me 6S-Me 118- 411 119 151imidazo[1,2-a]pyridin-2-yl H H 149- 353 150 152imidazo[1,2-a]pyridin-2-yl 3R-Me 5S-Me 171- 381 173 153imidazo[1,2-a]pyridin-2-yl 2R-Me 6S-Me 147- 381 149 1546-chloroimidazo[1,2- 2R-Me 6S-Me 76- 416, b]pyridazin-2-yl 84 418 1556-methylimidazo[1,2- 3R-Me 5S-Me 164- 395 a]pyridin-2-yl 165 156benzoxazol-2-yl 2R-Me 6S-Me 126- 382 127 157 4-cyanophenyl 2R-Me 6S-Me90- 366 100 158 6-hydroxy-pyridazin-3-yl 2R-Me 6S-Me 359

Example 159

1-{4-[2-(1R-Hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-2-(6-methyl-pyridin-3-yloxy)-ethanone.

Step A:1R-[4-(4-Chloroacetyl-3R,5S-dimethyl-piperazin-1-yl)pyrimidin-2-yl]-ethylbutyrate. To a solution of1R-[4-(3R,5S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl butyrate(prepared according to the method of Preparation Three, 9.69 g, 31.3mmol) and triethylamine (4.74 g, 46.9 mmol) in chloroform (150 mL) wasadded dropwise chloroacetyl chloride (3.00 mL, 37.6 mmol) at 0° C. thenstirred at ambient temperature for 12 h under nitrogen atmosphere. Themixture was washed successively with saturated aqueous sodiumbicarbonate and water, and the organic, layer was dried over sodiumsulfate, treated with activated carbon, and filtered. The filtrate wasconcentrated to obtain an oil which was purified by flash chromatography(9:1 dichloromethane:methanol) to give the title compound of Example159, Step A as an oil, 8.98 g (75%). ¹H NMR (CDCl₃, 300 MHz) δ 0.96 (d,3H), 1.32 (d, 6H), 1.59 (d, 3H), 1.71 (m, 2H), 2.40 (t, 2H), 3.28 (m,2H), 4.28 (s, 2H), 4.35 (m, 4H), 5.68 (q, 1H), 6.41 (d, 1H), 8.23 (d,1H); MS (CI) 383, 385 (MH⁺).

Step B:1R-(4-{3R,5S-Dimethyl-4-[(6-methyl-pyridin-3-yloxy)-acetyl]-piperazin-1-yl}-pyrimidin-2-yl)-ethylbutyrate. To a suspension of sodium hydride (60% dispersion in oil, 0.05g, 1.3 mmol) in tetrahydrofuran (2 mL) was added a solution of6-methyl-3-pyridinol (0.14 g, 1.3 mmol) in tetrahydrofuran (3 mL) at 0°C. under nitrogen atmosphere and stirred for 0.5 h warming to ambienttemperature. Next, a solution of1R-[4-(4-chloroacetyl-3R,5R-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethylbutyrate (prepared according to the method of Example 159, Step A, 0.40g, 1.1 mmol) in tetrahydrofuran (2 mL) was added and refluxed for 1 h.The mixture was diluted with dichloromethane and washed with saturatedaqueous sodium bicarbonate, dried over sodium sulfate and filtered. Thefiltrate was evaporated to an oil which was purified by flashchromatography (9:1 dichloromethane:methanol) to give the title compoundof Example 159, Step B as an oil, 0.31 g (66%). ¹H NMR (CDCl₃, 300 MHz)δ 0.96 (d, 3H), 1.32 (d, 6H), 1.59 (d, 3H), 1.71 (m, 2H), 2.40 (t, 2H),2.46 (s, 3H), 3.28 (m, 2H), 3.78 (s, 2H), 4.35 (m, 4H); 5.68 (q, 1H),6.41 (d, 1H), 6.83 (m, 1H), 7.14 (m, 1H), 8.08, (d, 1H), 8.23, (d, 1H);MS (Cl) 456 (MH⁺).

Step C:1-{4-[2-(1R-Hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-2-(6-methyl-pyridin-3-yloxy)-ethanone.1R-(4-{3R,5S-Dimethyl-4-[(6-methyl-pyridin-3-yloxy)-acetyl]-piperazin-1-yl}-pyrimidin-2-yl)-ethylbutyrate, (prepared according to the method of Example 159, Step B, 0.30g, 0.65, mmol) was combined with concentrated hydrochloric acid (3 mL)and stirred at, ambient temperature for 6 h. The mixture was neutralizedwith 6 N aqueous sodium hydroxide to pH 9 and extracted twice with ethylacetate. The organic extract was washed once with water, dried oversodium sulfate, and filtered. The filtrate was concentrated to an oilwhich was purified by flash chromatography (9:1dichloromethane:methanol) to give the title compound as a white foam,0.14 g (55%). ¹H NMR, (CDCl₃, 300 MHz) δ 1.38 (d, 6H), 1.55 (d, 3H),2.46 (s, 3H), 3.28 (m, 2H), 3.76 (s, 2H), 4.35-4.65 (m, 4H), 4.67 (q,1H), 6.38 (d, 1H), 6.83 (m, 1H), 7.11 (m, 1H), 8.08°, (d, 1H), 8.21 (d,1H); mp: 55-65° C.; MS (CI) 330 (MH⁺); [α]_(D) +16.0 (c 1.0, MeOH).

Example 160

1-[4-[2-(1R-Hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl]-2-(pyrimidin-2-ylsulfanyl)-ethanone.

Example 160 was prepared from the appropriate starting materials in amanner analogous to example 159. ¹H NMR (CDCl₃, 300 MHz) δ 1.38 (m, 6H),1.48 (d, 3H), 3.28 (m, 2H), 3.96 (s, 2H), 4.35 (m, 4H), 4.654.97 (m,3H), 6.28 (d, 1H), 6.93 μm, 1H), 7.11 (m, 1H), 8.21 (d, 1H), 8.45, (m,2H); mp: 60-70° C.; MS (CI) 389 (MH⁺); [α]_(D) +16.8 (c 1.0, MeOH).

Example 161

4-[2-(1R-Hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carboxylicacid, phenyl ester.

Step A:4-[2-(1R-Butyryloxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carboxylicacid phenyl ester. To a solution of1R-[4-(3R,5S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl butyrate(prepared according to the method of Preparation Three, 0.30 g, 0.98mmol) and triethylamine (0.20 g, 1.9 mmol) in dichloromethane (5 mL) wasadded phenyl chloroformate (0.76 g, 4.8 mmol) and stirred at ambienttemperature for 2 h under nitrogen atmosphere. The mixture was washedsuccessively with saturated aqueous sodium bicarbonate and water, andthe organic layer was dried over sodium sulfate and filtered. Thefiltrate was concentrated to obtain an oil which was purified by flashchromatography (9:1 dichloromethane:methanol) to give the title compoundof Example 161, Step A as an oil, 0.35 g (84%). ¹H NMR (CDCl₃, 300 MHz)δ 0.96 (d, 3H), 1.32 (d, 6H), 1.59 (d, 3H), 1.71 (q, 2H), 2.40 (t, 2H),3.28 (m, 2H), 4.35 (m, 4H), 5.68 (q, 1H), 6.41 (d, 1H), 7.12 (d, 2H),7.22 (m, 1H), 7.35 (m, 2H), 8.23 (d, 1H); MS (CI) 427 (MH⁺); [α]_(D)+39.6 (c 1.0, MeOH).

Step B:4-[2-(1R-Hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carboxylicacid Phenyl ester.4-[2-(1R-Butyryloxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carboxylicacid phenyl ester (prepared according to the method of Example 161, StepA, 0.31 g, 0.70 mmol) was combined with concentrated hydrochloric acid(5 mL) and stirred at ambient temperature for 6 h. The mixture wasneutralized with 6 N aqueous sodium hydroxide to pH 9 and extractedtwice with ethyl acetate. The organic extract was washed once withwater, dried over sodium sulfate and filtered. The filtrate wasconcentrated to an oil which was purified by flash chromatography (9:1dichloromethane:methanol) to give the title compound as a white solid,0.12 g (81%). ¹H NMR (CDCl₃, 300 MHz) δ 1.41 (d, 6H), 1.51 (d, 3H), 3.34(m, 2H), 4.43 (m, 2H), 4.52 (m, 2H), 4.71 (q, 1H), 6.46 (d, 1H), 7.12(m, 2H), 7.23 (m, 1H), 7.35 (m, 2H), 8.23 (d, 1 Hz; MS (CI) 357 (MH⁺);[α]_(D) +16.9 (c 1.0, MeOH).

Example 162

4-[2-(1R-Hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carboxylicacid Pyridin-3-yl ester.

Step A:4-[2-(1R-Hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carbonylchloride. To a solution of1R-[4-(3R,5S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl butytate(prepared according to the method of Preparation Three, 3.61, 11.8 mmol)and pyridine (0.93 g, 11.8 mmol) in dichloromethane (50 mL) was addedtriphosgene (1.17 g, 3.9 mmol) and stirred at ambient temperature for 16h under nitrogen atmosphere. The mixture was washed successively withsaturated aqueous sodium bicarbonate and water, and the organic layerwas dried over sodium sulfate and filtered. The filtrate wasconcentrated to obtain an oil which was purified by flash chromatography(ethyl acetate) to give the title compound of Example 162, Step A as ayellow oil, 2.12 g, (51%). ¹H NMR (CDCl₃, 300 MHz) δ 0.90 (t, 3H), 1.31(d, 6H), 1.56 (d, 3H), 1.68 (m, 2H), 2.38 (t, 2H), 3.21 (m, 2H),3.88-4.40 μm, 4H), 5.66 (q, 1H), 6.43 (d, 1H), 8.22 (d, 1H); MS (CI)369, 371 (MH⁺).

Step B:{4-[2-(1R-Butyryloxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine}-1-carboxylicacid Pyridin-3-yl ester. To a suspension of sodium hydride (60%dispersion in oil, 0.046 g, 1.15 mmol) in anhydrous tetrahydrofuran (8mL) was added 3-hydroxypyridine (0.11 g, 1.15 mmol) at 0° C. After ahomogeneous solution was obtained, a solution of4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carbonylchloride (prepared according to the method of Example 162, Step A, 0.36g, 0.96 mmol) in tetrahydrofuran (3 mL) was added at 0° C. and thismixture was warmed to ambient temperature, then heated to reflux for 6h. The mixture was quenched in water and extracted twice with ethylacetate. The combined organic layers were dried over sodium sulfate andfiltered. The filtrate was concentrated to obtain an oil, which waspurified by flash chromatography (ethyl acetate) to give the titlecompound of Example 162, Step B as a semi-solid, 0.31 g (78%). ¹H NMR(CDCl₃, 300 MHz) δ 0.90 (t, 3H), 1.35 (m, 6H), 1.61 (d, 3H), 1.69 (m,2H), 2.41 (t, 2H), 3.30 (m, 2H), 4.11-4.38 (m, 4H), 5.69 (q, 1H), 6.41(d, 1H), 7.32 (m, 1H), 7.52 (m, 1H), 8.22 (d, 1H), 8.46 (s, 1H), 8.48,(d, 1H); MS (CI) 428 (MH⁺).

Step C:4-[2-(1R-Hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carboxylicacid Pyridin-3-yl ester.{4-[2-(1R-Butyryloxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine}-1-carboxylicacid pyridin-3-yl ester (prepared according to the method of Example162, Step B, 0.31 g, 0.70 mmol) was combined with concentratedhydrochloric acid (5 mL) and stirred at ambient temperature for 6 h. Themixture was neutralized with 6 N aqueous sodium hydroxide to pH 9 andextracted twice with ethyl acetate. The extract was washed once withwater, dried over sodium sulfate and filtered. The filtrate wasconcentrated to an oil which was purified by flash chromatography (9:1dichloromethane:methanol) to give the title compound as a white solid,0.12 g (81%). ¹H NMR (CDCl₃, 300 MHz) δ 1.41 (d, 6H), 1.51 (d, 3H), 3.33(m, 2H), 4.25-4.45 (m, 4H), 4.71 (q, 1H), 6.43 (d, 1H), 7.33 (m, 1H),7.56 (m, 1H), 8.23 (d, 1H), 8.25 (d, 1H), 8.48 (d, 1H); MS (CI) 358(MH⁺); [α]_(D) +18.5 (c 1.0, MeOH).

Example 163

4-[2-(1R-Hydroxy-ethyl)-pyrimidin-4-yl]-2R-phenyl-piperazine-1-carboxylicacid pyridin-3-yl ester.

Step A: 1R-[4-(3R-phenyl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl butyrate.To a solution of (R)-2-phenylpiperazine (0.48 g, 3.0 mmol, Indian J.Chem. Sect. B 1994, 33, 285) and triethylamine (1.21 g, 12.0 mmol) intetrahydrofuran (10 mL) was added (R)-1-(4-chloropyrimidin-2-yl)-ethylbutyrate (prepared according to the method of Preparation Seven, 0.68 g,3.0 mmol) and stirred at ambient temperature for 18 h. The mixture waspoured into saturated aqueous sodium bicarbonate and extracted withethyl acetate. The combined organic layer was dried over sodium sulfateand filtered. The filtrate was concentrated to obtain a crude productwhich was purified by flash chromatography (95:5dichloromethane:methanol) to give the title compound of Example 163,Step A as a viscous oil, 0.70 g (67%) ¹H NMR (CDCl₃, 300 MHz) δ 0.95 (t,3H); 1.56 (d, 3H), 1.67 (m, 2H), 2.40 (t, 2H), 3.55 (m, 2H), 4.0 (m,2H), 4.32 (m, 2H), 4.70 (m, 1H), 5.69 (q, 1H), 6.49 (d, 1H), 7.40 (m,5H), 8.21 (d, 1H); MS (CI) 355 (MH⁺).

Step B:4-[2-(1R-Butyryloxy-ethyl)-pyrimidin-4-yl]-2R-phenyl-piperazine-1-carboxylicacid pyridin-3-yl ester. To a solution1R-[4-(3R-phenyl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl butyrate(prepared according to the method of Example 163, Step A, 0.22 g, 0.6mmol) and triethylamine (0.31 g, 3.1 mmol) in toluene (5 mL) was addeddipyridin-3-yl carbonate (0.67 g, 3.1 mmol) and heated to reflux for 3h. The mixture was poured into saturated aqueous sodium bicarbonate, theorganic layer was separated and the aqueous layer was extracted withethyl acetate. The combined organic layers were dried over sodiumsulfate and filtered. The filtrate was concentrated to obtain a crudeproduct which was purified by flash chromatography (9:1 dichloromethanemethanol) to give the title compound of Example 163, Step B as a yellowoil, 0.22 g (73%). MS (CI) 476 (MH⁺).

Step C:4-[2-(1R-Hydroxy-ethyl)-pyrimidin-4-yl]-2R-phenyl-piperazine-1-carboxylicacid Pyridin-3-yl ester.4-[2-(1R-Butyryloxy-ethyl)-pyrimidin-4-yl]-2R-phenyl-piperazine-1-carboxylicacid pyridin-3-yl ester (prepared according to the method of Example163, Step B, 0.21 g, 0.44 mmol) was combined with concentratedhydrochloric acid (2 mL) and stirred at ambient temperature for 6 h. Themixture was neutralized with 6 N aqueous sodium hydroxide to pH 9 andextracted twice with ethyl acetate. The combined extracts were washedonce with water, dried over sodium sulfate and filtered. The filtratewas concentrated to an oil which was purified by flash chromatography(9:1 dichloromethane:methanol) to give the title compound as a whitesolid, 0.13 g (73%). ¹H NMR (CDCl₃, 300 MHz) δ 1.55 (d, 3H), 3.55 (m,2H), 4.0 (m, 2H), 4.32 (m, 2H), 4.71 (m, 1H), 4.75 (q, 1H), 6.40 (d,1H), 7.18-7.41 (m, 7H), 8.24 (d, 1H), 8.35 (br s, 1H), 8.45 (d, 1H); MS(CI) 406 {MH⁺).

Examples 164 to 173

Examples 164 to 173 were prepared from the appropriate startingmaterials in a manner analogous to the method of Example 163.

Ex- am- mp ple R⁷ R⁶ Ar¹ (° C.) MS (MH⁺) 164 3R-Me 5S-Me phenyl 357 1653R-Me 5S-Me 2-methyl-pyridin-3-yl 65- 372 75 166 H H pyridin-3-yl 107-330 110 167 3R-Me 5S-Me 2-chloro-pyridin-3-yl 60- 392, 394 70 168 3R-Me5S-Me 5-chloro-pyridin-3-yl 65- 392, 394 69 169 3R-Me 5S-Meisoquinolin-5-yl 60- 407 70 170 3R-Me 5S-Me 4-chloro-pyridin-3-yl 60-392, 394 70 171 3R-Me 5S-Me 6-methyl-pyridin-3-yl 60- 372 70 172 2RS- Hpyridin-3-yl 388 CH₂OMe 173 2RS-CO₂Et H pyridin-3-yl 402

Example 174

(R)-4-Benzyl-1-[2-(1-hydroxy-ethyl)-pyrimidin-4-yl]-piperidin-4-ol.

Step A:(R)-1-[4-(4-Benzyl-4-hydroxy-piperidin-1-yl)-pyrimidin-2-yl]-ethylacetate. To a solution of 4-benzyl-4-hydroxypiperidine (0.95 g, 5.0mmol) and triethylamine (0.51 g, 5.0 mmol) in dichloromethane (10 mL)was added (R)-1-(4-methanesulfonyloxy-pyrimidin-2-yl)-ethyl butyrate(prepared according to the method of Preparation Eight, 1.23 g, 4.0mmol) and stirred at ambient temperature for 18 h. The mixture waswashed once with water, once with saturated aqueous sodium chloride andthe organic layer was dried over sodium sulfate and filtered. Thefiltrate was evaporated to an oil which was purified by flashchromatography (95:5 dichloromethane:methanol) to give the titlecompound of Example 174, Step A as a viscous oil, 0.9 g (52%). ¹H NMR(CDCl₃, 300 MHz), 0.95 (t, 3H), 1.53 (d, 3H), 1.65-1.78 (m, 4H), 1.88(m, 2H), 2.08 (m, 2H), 2.48 (t, 2H), 3.45 (m, 2H), 4.42 (br s, 1H), 5.68(q, 1H), 6.41 (d, 1H), 7.30-7.48 (m, 5H), 8.18 (d, 1H); MS (CI) 884(MH⁺).

Step B:(R)-4-Benzyl-1-[2-(1-hydroxy-ethyl)-pyrimidin-4-yl]-piperidin-4-ol. To asolution of (R)-1-[4-(4-benzyl-4-hydroxy-piperidin-1yl)-pyrimidin-2-yl]-ethyl butyrate (prepared accordirig to the method ofExample 174, Step A, 0.20 g, 0.52 mmol) in methanol (5 mL) was added 1 Naqueous sodium hydroxide (1 mL) and stirred for 4 h at ambienttemperature. The mixture was diluted with dichloromethane and washedonce with water, once with saturated aqueous sodium chloride and theorganic layer was dried over sodium sulfate and filtered. The filtratewas evaporated to give the title compound as a foam, 0.129 g (68%). ¹HHNMR (CDCl₃, 300 MHz) δ 1.49 (d, 3H), 1.74 (br s, 2H), 1.82 (m, 2H),2.08 (m, 2H), 3.42 (m, 2H), 4.42 (br s, 1H), 4.71 (q, H), 6.43 (d, 1H),7.33-7.48 (m, 5H), 8.21 (d, 1H); MS (CI) 314 (MH⁺).

Example 175

(R)-4-phenyl-1-[2-(1-hydroxy-ethyl)-pyrimidin-4-yl]-piperidin-4-ol.

Example 175 was prepared from the appropriate starting materials in amanner analogous to the method of Example 174. mp: 114° C.; MS (CI) 300(MH⁺).

Example 176

(R)-1-[4-[4-(3-Chlorobenzylidene)-piperidin-1-yl]-pyrimidin-2-yl}-ethanol.

Step A: 1-[4-(3-Chlorobenzylidene)-piperidine-1-yl]-1-carboxylic acidtert-butyl ester. To a suspension of 4-chlorobenzyltriphenylphosphoniumchloride (4.23 g, 10.0 mmol) in tetrahydrofuran (40 mL) was addedn-butyllithium in hexanes (2.5 M in hexanes, 4.4 mL, 11.0 mmol) at 0° C.under nitrogen atmosphere and stirred 0.5 h. A solution of4-oxo-piperidine-1-carboxylic acid tert-butyl ester (prepared accordingto the method of Example 101, Step A, 1.99 g, 10.0 mmol) intetrahydrofuran (10 mL) was added at 10-15° C. and warmed to ambienttemperature. The mixture was evaporated to an oil which was purified byflash chromatography (9:1 hexanes:ethyl acetate) to give the titlecompound of Example 176, Step A as an oil, 2.63 g (85%). ¹H NMR (CDCl₃,300 MHz) δ 1.39 (s, 9H), 2.48 (m, 2H), 2.57 (m, 2H), 3.68-3.82 (m, 4H),6.36 (s, 1H), 7.08 (m, 1H), 7.12-7.28 (m, 3H); MS (CI) 308 (MH⁺).

Step B: 4-(3-Chloro-benzylidene)-piperidine hydrochloride. To a solutionof 1-[4-(3-chlorobenzylidene)-piperidine-1-yl]-1-carboxylic acidtert-butyl ester (prepared according to the method of Example 176, StepA, 2.5 g, 8.1 mmol) in dichloromethane (20 mL) was added hydrogenchloride (4 M in dioxane, 4.0 mL, 16.0 mmol) at ambient temperature andstirred for 4 h. The mixture was evaporated to dryness, suspended inethyl ether and filtered to give the title compound of Example 176, StepB as a white solid, 1.63 g (82%). ¹H NMR (CDCl₃/D₂O, 300 MHz); δ 2.48(m, 2H), 2.57 (m, 2H), 3.63 (m, 2H), 3.77 (m, 2H), 6.36 (s, 1H), 7.10(m, 1H), 7.12-7.28 (m, 3H); mp: 147-151° C.

Step C:(R)-1-{4-[4-(3-Chloro-benzylidene)-piperidin-1-yl]-pyrimidin-2-yl}-ethylbutyrate. To a solution of 4-(3-chlorobenzylidene)-piperidinehydrochloride (prepared according to the method of Example 176, Step B,0.46 g, 2.0 mmol) and triethylamine (0.61 g, 6.0 mmol) indichloromethane (10 mL) was added (R)-1-(4-chloropyrimidin-2-yl)-ethylacetate (prepared according to the method of Preparation Five, 0.54 g,2.2 mmol) and stirred at ambient temperature for 12 h. The mixture waswashed successively with saturated aqueous sodium bicarbonate and water,and the organic layer was dried over sodium sulfate and filtered. Thefiltrate was concentrated to obtain a crude product which was purifiedby flash chromatography (95:5 dichloromethane:methanol) to give thetitle compound of Example 176, Step C as a viscous oil, 0.64 g (80%). ¹HNMR (CDCl₃, 300 MHz) δ 0.95 (d, 6H), 1.51 (d, 3H), 1.68 (m, 2H) 2.35 (m,2H), 2.47-2.64 (m, 4H), 3.67-3.75 (m, 4H), 5.68 (q, 1H), 6.36 (s, 1H),6.40 (d, 1H), 6.98 (m, 1H), 7.12-7.28 (m, 3H), 8.18 (m, 1H); MS (CI) 400(MH⁺).

Step D:(R)-1-{4-[4-(3-Chlorobenzylidene)-piperidin-1-yl]-pyrimidin-2-yl}-ethanol.To a solution of(R)-1-{4-[4-(3-chloro-benzylidene)-piperidin-1-yl]-pyrimidin-2-yl}thylbutyrate (prepared according to the method of Example 176, Step C, 0.62g, 1.55 mmol) in methanol (8 mL) was added 1 N aqueous sodium hydroxide(1 mL) then stirred for 4 h at ambient temperature. The mixture wasdiluted with chloroform and washed once with water, once with saturatedaqueous sodium chloride and the organic layer was dried over sodiumsulfate and filtered. The filtrate was concentrated to obtain a crudeproduct which was purified by flash chromatography (95:5dichloromethane:methanol) to give the title compound as a white solid,0.31 g (61%). ¹H NMR (CDCl₃, 300 MHz) δ 1.51 (d, 3H), 2.46 (m, 2H), 2.56(m, 2H), 3.07 (m, 2H), 3.77 (m, 2H), 4.35 (d, 1H), 4.69 (q, 1H), 6.36(s, 1H), 6.40 (d, 1H), 7.07 (m, 1H), 7.12-7.28 (m, 3H), 8.18 (m, 1H);mp: 45-55° C.; MS (CI) 330 (MH⁺); [α]_(D) +16.8 (c 1.0, MeOH).

Examples 177 to 181

Examples 177 to 181 were prepared from the appropriate startingmaterials in a manner analogous to the method of Example 176.

Example R⁴² R^(42a) mp (° C.) MS (MH⁺) 177 4-chlorophenyl H 330, 332 178(E)-2-phenyl-ethen-1-yl H 322 179 benzoyl H 44-59 324 180 phenyl phenyl108-109 372 181 phenyl pyrid-2-yl  98-101 373

Example 182

(R)-1-[4-(4-pyridin-2-ylmethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethanol.

Step A:(R)-1-[4-(4-pyridin-2-ylmethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethylacetate.

To a solution of (R)-1-[4-piperazin-1-yl)-pyrimidin-2-yl]-ethyl acetate(prepared according to the method of Preparation Two, 1.55 g, 6.2 mmol)and triethylamine (0.86 mL, 6.2 mmol) in tetrahydrofuran (20 mL) wasadded 2-picoylchloride hydrochloride (0.01 g, 6.2 mmol) at ambienttemperature and stirred for 1 h. The mixture was diluted with water andextracted twice with ethyl acetate. The combined extracts were driedover magnesium sulfate, filtered, and the filtrate was concentrated, toan oil which was purified by flash chromatography (95:5dichloromethane:methanol) to give the title compound of Example 182,Step A, 0.98 g (46%). ¹H NMR (CDCl₃, 300 MHz) δ 1.58 (d, 3H), 2.15 (s,3H) 2.62 (t, 4H), 3.72 (t, 4H), 3.75 (s, 2H) 5.67 (q, 1H), 6.35 (d, 1H),7.22 (m, 1H), 7.46 (d, 1H), 7.73 (m, 1H), 8.21 (d, 1H), 8.62 (d, 1H); MS(CI) 342 (MH⁺).

Step B:(R)-1-[4-(4-pyridin-2-ylmethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethanol.To a solution of(R)-1-[4-(4-pyridin-2-ylmethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethylacetate (prepared according to the method of Example 182, Step A, 0.14g, 0.33 mmol) in dioxane (6 mL) was added at ambient temperature 6 Naqueous potassium hydroxide (0.5 mL). After stirring for 3 h thesolution was diluted with ethyl acetate and washed twice with water. Theorganic layer was separated, dried over magnesium sulfate, filtered, andthe filtrate was concentrated to give the title compound as a whitesolid, 0.09 g (69%). ¹H NMR (CDCl₃, 300 MHz) δ 1.52 (d, 3H), 2.38-2.59(m, 4H), 3.72-3.77 (m, 6H), 4.69 (q, 1H), 6.37 (d, 1H), 7.22 (d, 1H),7.41 (d, 1H), 7.69 (m, 1H), 8.21 (d, 1H) 8.58, (d, 1H); mp: 68-70° C.;MS (CI) 300 (MH⁺); [α]_(D) +16.2 (c 1.0, MeOH).

Examples 183 to 187

Examples 183 to 187 were prepared from the appropriate startingmaterials in a manner analogous to the method of Example 182.

Example R⁹ mp (° C.) MS (MH⁺) 183 phenylmethyl 299 184isoquinolin-2-yl-methyl 350 185 benzothien-2-yl-methyl 355 186benzothiazol-2-yl-methyl 356 187 benzofuran-2-yl-methyl 339

Example 188

1R-{4-[2R,6S-Dimethyl-4-(2-[1,2,4]triazol-1-yl-pyrimidin-4-yl]-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.

Step A: 4-(3R,5S-Dimethyl-piperazin-1-yl)-2-methanesulfonyl-pyrimidine.To a solution of cis-2,6-dimethylpiperazine (10.7 g, 94.1 mmol) andtriethylamine (9.52 g, 94.1 mmol) in chloroform (300 mL) was added4-chloro-2-methanesulfonylpyrimidine 15.1 g, 78.4 mmol; Heterocycles1985, 23, 611) at ambient temperature and stirred for 1 h. The mixturewas partitioned with saturated aqueous sodium bicarbonate and theseperated organic layer was washed once with water, once with saturatedaqueous sodium chloride and the organic layer was dried over sodiumsulfate and filtered. The filtrate was evaporated to an orange solidwhich was slurried in ethyl ether and filtered to give the titlecompound of Example 188, Step A as a white solid, 15.4 g (73%). ¹H NMR(CDCl₃, 400 MHz) δ 1.01 μm, 6H), 2.35-2.78 (m, 4H), 2.85 (s, 2H), 6.81(d, 1H), 8.2 (d, 1H); mp: 182-183° C.; MS (CI) 301 (MH⁺).

Step B:4-(3R,5S-Dimethyl-piperazin-1-yl)-2-[1,2,4]triazol-1-yl-pyrimidine. To aslurry of sodium hydride (60% dispersion in oil, 0.37 g, 9.4 mmol) indimethylformamide (5 mL) was added a solution of 1,2,4-triazole (0.67 g,9.4 mmol) in dimethylformamide (4 mL) at 0° C. under nitrogenatmosphere. After 10 min, a solution of4-(3R,5S-dimethyl-piperazin-1-yl)-2-methanesulfonyl-pyrimidine (preparedaccording to the method of Example 188, Step A, 2.54 g, 9.4 mmol) inwarm dimethylformamide (5 mL) was added dropwise and stirred at ambienttemperature for 2 h then heated to 100° C. for 0.5 h. The mixture wasquenched in saturated aqueous sodium bicarbonate and extracted twicewith ethyl acetate. The combined extracts were washed once with water,once with saturated aqueous sodium chloride and the organic layer wasdried over sodium sulfate and filtered. The filtrate was evaporated toan oil which was purified by flash chromatography (9:1dichloromethane:methanol) to give the title compound of Example 188,Step B as an oil, 0.50 g (62%). ¹H NMR (CDCl₃, 400 MHz) 61.01 (m, 6H),2.35-2.88 (m, 5H), 3.32 (m, 1H), 6.81 (d, 1H), 8.16-8.23 (m, 2H), 9.25(d, 1H); MS (CI) 260 (MH⁺).

Step C:1R-{4-[2R,6S-Dimethyl-4-(2-[1,2,3]triazol-1-yl-pyrimidin-4-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethylbutyrate. To a solution of4-(3R,5S-dimethyl-piperazin-1-yl)-2-[1,2,4]triazol-1-yl-pyrimidine(prepared according to the method of Example 188, Step B, 0.46 g, 1.8mmol) in acetonitrile (3 mL) was added(R)-1-(4-methanesulfonyloxy-pyrimidin-2-yl)-ethyl butyrate (preparedaccording to the method of Preparation Eight, 0.57 g, 2.0 mmol) andheated to reflux for 6 h under nitrogen atmosphere. The mixture wasquenched in saturated aqueous sodium bicarbonate and extracted twicewith ethyl acetate. The combined extracts were washed once with water,once with saturated aqueous sodium chloride and the organic layer wasdried over sodium sulfate and filtered. The filtrate was evaporated toan oil which was purified by flash chromatography (9:1dichloromethane:methanol) to give the title compound of Example 188,Step C as an oil, 0.22 g (54%). ¹H NMR (CDCl₃, 400 MHz) δ 0.95 (t, 3H),1.51 (m, 6H), 1.54 (d, 3H), 1.63 (m, 2H), 2.38 (t, 2H), 3.38 (m, 2H),4.33-4.64 (m, 4H), 5.68 (q, 1H), 6.28 (d, 1H), 6.58 (d, 1H), 8.10 (s,1H), 8.26-8.32 (m, 2H), 9.10 (d, 1H); MS (CI) 452 (MH⁺); [α]_(D) +50.0(c 1.0, MeOH).

Step D:1R-{4-[2R,6S-Dimethyl-4-(2-[1,2,4]triazol-1-yl-pyrimidin-4-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.1R-{4-[2R,6S-Dimethyl-4-(2-[1,2,3]triazol-1-yl-pyrimidin-4-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethylbutyrate (prepared according to the method of Example 188, Step C, 0.18g, 0.40 mmol) was combined with concentrated hydrochloric acid (2 mL)and stirred at ambient temperature for 4 h. The mixture was quenched insaturated aqueous sodium bicarbonate and extracted twice with ethylacetate. The combined extracts were washed once with water, once withsaturated, aqueous sodium chloride and the organic layer was dried oversodium sulfate and filtered. The filtrate was evaporated to an oil whichwas purified by flash chromatography (9:1 dichloromethane:methanol) togive the title compound as a white solid, 0.13 g (87%). ¹H NMR (CDCl₃,400 MHz) δ 1.31 (d, 6H), 1.51 (d, 3H), 3.42 (m, 2H), 4.42-4.73 (m, 5H),6.41 (d, 1H), 6.56 (d, 1H), 8.12 (s, 1H), 8.24 (d, 1H), 8.30 (d, 1H),9.10 (s, 1H); MS (CI) 382 (MH⁺); [α]_(D) +18.6 (c 1.0, MeOH).

Examples 189 to 195

Examples 189 to 195 were prepared from the appropriate startingmaterials in a manner analogous to the method of Example 188.

Ex- am- mp ple R¹¹ R⁷ R⁶ (° C.) MS (MH⁺) 189 2-hydroxyphenyl 2R-Me 6S-Me60- 407 70 190 imidazol-1-yl 2R-Me 6S-Me 60- 381 70 191[1,2,3]triazol-1-yl 2R-Me 6S-Me 70- 382 80 192 pyrrol-1-yl 2R-Me 6S-Me70- 380 80 193 4-methylimidazol-1-yl 2R-Me 6S-Me 70- 395 80 1942-methylimidazol-1-yl 2R-Me 6S-Me 70- 395 80 1952,4-dimethylimidazol-1-yl 2R-Me 6S-Me 70- 409 80

Example 196

1R-{4-[2R,6S-Dimethyl-4-(4-[1,2,4]triazol-1-yl-pyrimidin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}ethanol

Step A: 2-Thiomethyl-4-[1,2,4]triazol-1-yl-pyrimidine. To a slurry ofsodium hydride (60% dispersion in oil, 24.2 g, 605 mmol) indimethylformamide (800 mL) was added a solution of 1,2,4-triazole (0.67g, 9.4 mmol) in dimethylformamide (4.0 mL) at 0° C. under nitrogenatmosphere. After 1.0 min, a solution of4-chloro-2-methylthio-pyrimidine (97.2 g, 605 mmol) in dimethylformamide(200 mL) was added dropwise at 10° C. and stirred at ambient temperaturefor 14 h. The mixture was quenched in water and the solid precipitatewas filtered off and dried under vacuum to give the title compound ofExample 196, Step A as a white solid, 113 g (94%). ¹H NMR (CDCl₃, 400MHz) δ 2.82 (s, 3H), 6.82 (d, 1H), 8.18 (d, 1H), 8.19 (s, 1H), 9.35 (s,1H); mp: 125-126° C.; MS (CI) 194 (MH⁺).

Step B: 2-Methanesulfonyl-4-[1,2,4]triazol-1-yl-pyrimidine. To amechanically stirred suspension of 3-chloroperoxybenzoic acid (75%, 127g, 551 mmol) in chloroform (625 mL) was added a solution of2-thiomethyl-4-[1,2,4]triazol-1-yl-pyrimidine (prepared according to themethod of Example 196, Step A, 50.7 g, 262 mmol) in chloroform (625 mL)and stirred at ambient temperature for 16 h. The mixture was filteredand the filtrate was washed six times with saturated aqueous sodiumcarbonate. The organic layer was dried over sodium sulfate, filtered,and concentrated to give the title compound of Example 196, Step B as awhite solid, 37.8 g (64%). ¹H NMR (CDC₃, 400 MHz) δ 3.62 (s, 3H), 6.82(d, 1H), 8.19 (s, 1H), 8.24 (d, 1H), 9.35 (s, 1H); mp: 135-136° C.; MS(CI) 226 (MH⁺).

Step C:2-(3R,5S-Dimethyl-piperazin-1-yl)-4-[1,2,4]triazol-1-yl-pyrimidine.2-Methanesulfonyl-4-[1,2,4]triazol-1-yl-pyrimidine (prepared accordingto the procedure of Example 196, Step B, 32.5 g, 144 mmol) was combinedwith cis-2,6-dimethylpiperazine (34.5 g, 302 mmol) and heated neat at135° C. for 1 h, cooled, dissolved in 2 N aqueous hydrochloric acid andwashed once with ethyl acetate. The acidic aqueous layer was basified topH 9 with 6 N aqueous sodium hydroxide at 0° C. then extracted fourtimes with ethyl acetate. The combined extracts were washed once withwater, once with saturated aqueous sodium chloride and the organiclayer, was dried over sodium sulfate and filtered. The filtrate wasevaporated to an oil which crystallized from hexanes to give the titlecompound of Example 196, Step C as a white solid, 31.8 g (71%). ¹H NMR(CDCl₃, 400 MHz) δ 0.99 (d, 6H), 2.38 (m, 4H), 3.30 (s, 2H), 6.82 (d,1H), 8.18 (d, 1H), 8.19 (s, 1H), 9.35 (s, 1H); mp: 143-145° C.; MS (CI)260 (MH⁺).

Step D:1R-[4-[2R,6S-Dimethyl-4-(4-[1,2,4]triazol-1-yl-pyrimidin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl]-ethylbutyrate. To a solution of2-(3R,5S-dimethyl-piperazin-1-yl)-4-[1,2,4]triazol-1-yl-pyrimidine(prepared according to the method of Example 196, Step C, 8.33 g, 32.1mmol) in acetonitrile (30 mL) was added(R)-1-(4-trifluoromethanesulfonyloxy-pyrimidin-2-yl)-ethyl butyrate(prepared according to the method of Preparation Nine, 5.50 g, 16.1mmol) and heated to reflux for 3 h under nitrogen atmosphere. The cooledmixture was filtered and the solids were washed twice with ethylacetate. The combined extracts were washed once with water, once withsaturated aqueous sodium chloride and the organic layer was dried oversodium sulfate and filtered. The filtrate was evaporated to an oil whichwas purified by flash chromatography (99:1 dichloromethane:methanol) togive the title compound of Example 196, Step D as an oil, 3.61 g (50%).¹H NMR (CDCl₃, 400 MHz) δ 0.91 (d, 6H), 1.26 (t, 3H), 1.59 (d, 3H), 1.69(q, 2H), 2.40 (m, 2H), 3.40 (d, 2H), 4.60 (m, 4H), 5.70 (q, 1H), 6.39(d, 1H), 6.58 (d, 1H), 8.12 (s, 1H), 8.25 (d, 1H), 8.31 (d, 1H), 8.35(s, 1H); MS (CI) 452 (MH⁺).

Step E:1R-{4-[2R,6S-Dimethyl-4-(4-[1,2,4]triazol-1-yl-pyrimidin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.1R-{4-[2R,6S-Dimethyl-4-(4-[1,2,4]triazol-1-yl-pyrimidin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethylbutyrate (prepared according to the method of Example 196, Step D, 3.60g, 8.0 mmol) was combined with concentrated hydrochloric acid (10 mL)and stirred at ambient temperature for 4 h. The mixture was quenched insaturated aqueous sodium bicarbonate and extracted twice with ethylacetate. The combined extracts were washed once with water, once withsaturated aqueous sodium chloride and the organic layer was dried oversodium sulfate and filtered. The filtrate was evaporated to an oil whichwas purified by flash chromatography (99:1 dichloromethane:methanol) togive the title compound as a white solid, 2.35 g (77%). ¹H NMR (CDCl₃,400 MHz) δ 1.31 (d, 6H), 1.51 (d, 3H), 3.34 (m, 2H), 4.42 (m, 2H),4.68-4.82 (m, 3H), 6.42 (d, 1H), 7.11 (d, 1H), 8.11 (s, 1H), 8.23 (d,1H), 8.49 (d, 1H), 9.12 (s, 1H); mp: 181-182° C.; MS (CI) 382 (MH⁺).

Examples 197 to 200,

Examples 197 to 200 were prepared from the appropriate startingmaterials in a manner analogous to the method of Example 196.

Ex- am- ple R¹¹ R⁷ R⁶ mp(° C.) MS(MH⁺) 197 imidazol-1-yl 2R-Me 6S-Me60-70 381 198 morpholin-4-yl 2R-Me 6S-Me 70-80 400 199 pyrrolidin-1-yl2R-Me 6S-Me 70-80 384 200 4-methylpiperazin-1-yl 3R-Me 5S-Me 168-170 413

Example 201

1R-{4-[2R,6S-Dimethyl-4-(2-pyridin-3-yl-pyrimidin-4-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.

Step A: 2-pyridin-3-yl-pyrimidin-4-yl trifluoromethanesulfonate. To asolution of 2-pyridin-3-yl-3H-pyrimidin-4-one (150 mg, 0.87 mmol; J.Med. Chem. 1990, 33, 1230) and triethylamine (0.13 mL, 0.95 mmol) indichloromethane (3 mL) was added dropwise a solution oftrifluoromethanesulfonic anhydride (0.22 mL, 0.91 mmol) indichloromethane (2 mL) at 0° C. under nitrogen atmosphere. The mixturewas allowed to stir for 30 min at 0° C. then diluted withdichloromethane and washed once with water and the aqueous layer wasextracted twice with dichloromethane. The organic extracts werecombined, washed sequentially with saturated aqueous sodium carbonateand saturated aqueous sodium chloride, dried over sodium sulfate andfiltered. The filtrate was evaporated to give the title compound ofExample 201, Step A as an orange oil, 0.22 g (95%), that was usedwithout further purification.

Step B:1R-[4-[2R,6S-Dimethyl-4-(2-pyridin-3-yl-pyrimidin-4-yl)-piperazin-1-yl]-pyrimidin-2-yl]-ethanol.A solution of 2-pyridin-3-yl-pyrimidin-4-yl trifluoromethanesulfonate(prepared according to the method of Example 201, Step A, 0.15 g, 0.5mmol) in tetrahydrofuran (3 mL) at 0° C. was added dropwise to asolution of 1R-[4-(2R,6S-dimethyl-piperazin-1 yl)-pyrmidin-2-yl]-ethylbutyrate (prepared according to the method of Preparation Four, 0.15 g,0.45 mmol) in tetrahydrofuran (2 mL) and stirred for 1 h at ambienttemperature. The mixture was quenched in saturated aqueous sodiumbicarbonate and extracted twice with ethyl acetate. The combinedextracts were washed once with water, once with saturated aqueous sodiumchloride and the organic layer was dried over sodium sulfate andfiltered. The filtrate was evaporated to an oil and dissolved inconcentrated hydrochloric acid (3 mL) and stirred at ambient temperaturefor 4 h. The mixture was quenched in saturated aqueous sodiumbicarbonate and extracted twice with ethyl acetate. The combinedextracts were washed once with water, once with saturated aqueous sodiumchloride and the organic layer was dried over sodium sulfate andfiltered. The filtrate was evaporated to give the title compound as awhite foam, 0.091 g (48%). ¹H NMR (CDCl₃, 400 MHz) δ 1.31 (d, 6H), 1.51(d, 3H), 3.34 (m, 2H), 4.42-4.70 (m, 4H), 4.71 (q, 1H), 6.40 (d, 1H),6.56 (d, 1H), 7.37 (m, 1H), 8.22 (d, 1H), 8.36 (d, 1H), 8.62-8.68 (m,2H), 9.53 (m, 1H); mp: 61-70° C.; MS (CI) 392 (MH⁺).

Example 202

1R-(4-{2R,6S-Dimethyl-4-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol.

Step A:1R-[4-[4-(2-Methanesulfonyl-pyrimidin-4-yl)-2R,6S-dimethyl-piperazin-1-yl-pyrimidin-2-yl]-ethylbutyrate. To a solution of4-(3R,5S-dimethyl-piperazin-1-yl)-2-methanesulfonyl-pyrmidine (preparedaccording to the method of Example 188, Step A, 7.70 g, 14.3 mmol) inacetonitrile (30 mL) was added1R-(4-trifluoromethanesulfonyloxy-pyrimidin-2-yl)-ethyl butyrate(prepared according to the method of Preparation Nine, 5.50 g, 16.1mmol) and heated to reflux for 3 h under nitrogen atmosphere. The cooledmixture was filtered and the solids were washed twice with ethylacetate. The combined extracts were washed once with water, once withsaturated aqueous sodium chloride and the organic layer was dried oversodium sulfate and filtered. The filtrate was evaporated to an oil whichwas purified by flash chromatography (98:2 dichloromethane:methanol) togive the title compound of Example 202, Step A as an oil, 4.01 g (62%).¹H NMR (CDCl₃, 400 MHz) δ 0.93 (t, 3H), 1.21 (d, 6H), 1.55 (d, 3H), 1.64(q, 2H), 2.36 (t, 2H), 3.25 (s, 3H), 3.37 (m, 2H), 4.5-4.7 (m, 4H), 5.65(q, ₁H), 6.33 (d, 1H), 6.68 (d, 1H), 8.22 (d, 1H), 8.28 (d, 1H); MS (CI)463 (MH⁺).

Step B:1R-{4-[4-(2-Methanesulfonyl-pyrimidin-4-yl-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.1R-{4-[4-(2-Methanesulfonyl-pyrimidin-4-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethylbutyrate (prepared according to the method of Example 202, Step A, 0.42g, 0.9 mmol) wags combined with concentrated hydrochloric acid (3 mL)and stirred at ambient temperature for 4 h. The mixture was quenched insaturated aqueous sodium bicarbonate and extracted twice with ethylacetate. The combined extracts were washed once with water, once withsaturated aqueous sodium chloride and the organic layer was dried oversodium sulfate and filtered. The filtrate was evaporated to an oil whichwas purified by flash chromatography (99:1 dichloromethane:methanol) togive the title compound of Example 202, Step B as a white foam, 0.25 g(71%). ¹H NMR (CDCl₃, 400 MHz) δ 1.26 (d, 6H), 1.50 (d, 3H), 3.25 (s,3H), 3.41 (m, 2H), 4.5-4.7 (m, 5H), 6.37 (d, 1H), 6.71 (d, 1H), 8.24 (d,1H), 8.30 (d, 1H); MS (CI) 393 (MH⁺).

Step C:1R-(4-12R,6S-Dimethyl-4-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yl-piperazin-1-yl]-pyrimidin-2-yl)-ethanol.1R-(4-{4-(2-Methanesulfonyl-pyrimidin-4-yl)-2,6-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol(prepared according to the method of Example 202, Step B, 0.25 g, 6.4mmol) was combined with N-methylpiperazine (2.0 mL) and heated at 80° C.for 1 h under nitrogen atmosphere. The mixture was quenched in water andextracted twice with ethyl acetate. The combined extracts were washedonce with water, once with saturated aqueous sodium chloride and theorganic layer was dried over sodium sulfate and filtered. The filtratewas evaporated to an oil which was purified by flash chromatography(96:4 chloroform:methanol) to give the title compound as a white foam,0.11 g (41%). ¹H NMR (CDCl₃, 400 MHz) δ 1.31 (d, 6H), 1.51 (d, 3H), 2.47(s, 3H), 2.63 (m, 4H), 3.23 (m, 2H), 3.94 (m, 4H), 4.33 (m, 2H), 4.57(m, 2H), 4.71 (q, 1H), 5.96 (d, 1H), 6.46 (d, 1H), 7.98 (d, 1H), 8.23(d, 1H); mp: 60-70° C.; MS (CI) 413 (MH⁺).

Examples 203 to 207

Examples 203 to 207 were prepared from the appropriate startingmaterials in a manner analogous to the method of Example 202.

Ex- am- MS ple R¹¹ R⁷ R⁶ mp (° C.) (MH⁺) 203 morpholin-4-yl 2R-Me 6S-Me70-80 400 204 pyrrolidin-1-yl 2R-Me 6S-Me 70-80 384 2052,6-dimethylmorpholin- 2R-Me 6S-Me 428 4-yl 206 3,5-dimethylpiperidin-2R-Me 6S-Me 426 1-yl 207 5-methyl-furan-2-yl 2R-Me 6S-Me 123-128 395

Example 208

1R-(4-{3R,5S-Dimethyl-4-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol.

Step A:4-(4-Benzyl-2R,6S-dimethyl-piperazin-1-yl)-2-methanesulfonyl-pyrimidine.

To a solution of cis-1′-benzyl-3,5-dimethylpiperazine (24.9 g, 122 mmol,Org. Prep. Proceed. Int. 1976, 8, 19) in dimethylacetamide (60 mL) wasadded 4-chloro-2-methanesulfonyl pyrimidine (11.8 g, 61.3 mmol) andstirred for 16 h at 120° C. The mixture was partitioned between waterand ethyl acetate and the aqueous layer was extracted three times withethyl acetate. The combined organic layers were washed three times with1% aqueous copper sulfate, once with saturated aqueous sodium chlorideand; the organic layer was dried over sodium sulfate and filtered. Thefiltrate was evaporated to an orange solid which was slurried inisopropyl ether (100 mL) and filtered to give the title compound ofExample 208, Step A as an orange solid, 16.5 g (75%). ¹H NMR (CDCl₃, 300MHz) δ 1.35 (d, 6H), 2.25 (m, 2H), 2.76 (m, 2H), 3.23 (s, 3H), 3.53 (s,2H), 4.35-4.65 (m, 2H), 6.51 (d, 1H), 7.26 (m, 2H), 7.34 (m, 3H), 8.24(d, 1H); MS (CI) 361 (MH⁺).

Step B:4-(4-Benzyl-2R,6S-dimethyl-piperazin-1-yl)-2-(4-methylpiperazin-1-yl)-pyrimidine.4-(4-Benzyl-2R,6S-dimethylpiperazin-1-yl)-2-methanesulfonylpyrimidine(prepared according to the method of Example 208, Step A, 11.5 g, 31.9mmol) was combined with N-methylpiperazine (15 mL, 128 mmol) and heatedto 120° C. for 2 h. The mixture was diluted with ethyl acetate andwashed once with water, once with saturated aqueous sodium chloride andthe organic layer was dried over sodium sulfate and filtered. Thefiltrate was evaporated to give the title compound of Example 208, StepB as an orange solid, 14.7 g (84%). ¹H NMR (CDCl₃, 300 MHz) δ 1.30 (d,6H), 2.21 (m, 2H), 2.33 (s, 3H), 2.46 (m, 4H), 2.72 (d, 2H), 3.53 (s,2H), 3.78 (m, 4H), 4.31, (m, 2H), 5.79 (d, 1H), 7.24 (m, 2H), 7.31 (m,3H), 7.90 (d, 1H); MS (CI) 381 (MH⁺).

Step C:4-(2R,6S-Dimethyl-piperazin-1-yl)-2-(4-methylpiperazin-1-yl)-pyrimidine.To a solution of4-(4-benzyl-2R,6S-dimethylpiperazin-1-yl)-2-(4-methyl-piperazin-1-yl)-pyrimidine(prepared according to the method of Example 208, Step B, 9.8 g, 25.8mmol) in methanol (200 mL) and hydrochloric acid (1 N in ethyl ether,38.7 mL, 38.7 mmol) was added ammonium formate (16.3 g, 25.8 mmol).After stirring at ambient temperature for 5 min, 10% palladium on carbon(1.96 g, 20 wt % pre-wetted with isopropanol) was added and this mixturewas heated to reflux for 2 h. The cooled reaction was filtered and thefiltrate was concentrated to a solid, which was diluted with ethylacetate and washed twice with water, once with saturated aqueous sodiumchloride and the organic layer was dried over sodium sulfate andfiltered. The filtrate was evaporated to give the title compound ofExample 208, Step C as a clear oil, 6.01 g (81%). ¹H NMR (CDCl₃, 300MHz) δ 1.25 (s, 6H), 2.31 (s, 3H), 2.24-2.44 (m, 4H), 2.90 (m, 4H), 3.76(m, 4H), 4.25 (m, 2H), 5.79 (d, 1H), 7.90 (d, 1H); MS (CI) 291 (MH⁺).

Step D:1R-(4-{3R,5S-Dimethyl-4-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethylbutyrate. To a solution of4-(2R,6S-dimethyl-piperazin-1-yl)-2-(4-methyl-piperazin-1-yl)-pyrimidine(prepared according to the method of Example 208, Step C, 9.0 g, 31.1mmol) and triethylamine (6.5 g, 46.5 mmol) in dimethylformamide (90 mL)was added (R)-1-(4-chloro-pyrimidin 2-yl)ethyl butyrate (preparedaccording to the method of Preparation Seven, 7.78 g, 34.1 mmol) andheated to reflux for 3 h under nitrogen atmosphere. The cooled mixturewas filtered and the solids were washed twice with ethyl acetate. Thecombined extracts were washed once with water, once with saturatedaqueous sodium chloride and the organic layer was dried over sodiumsulfate and filtered. The filtrate was evaporated to an oil which waspurified by flash chromatography (95:5 chloroform:methanol) to give thetitle compound of Example 208, Step D as an oil, 11.4 g (76%). ¹H NMR(CDCl₃, 300 MHz) 80.95 (t, 3H), 1.18 (d, 6H), 1.54 (d, 3H), 2.23-2.35(m, 7H), 2.51 (m, 4H), 3.21 (m, 2H), 3.81 (m, 4H), 4.32 (m, 2H), 4.52(m, 2H), 5.65 (q, 1H), 5.82 (d, 1H), 6.38 (d, 1H), 7.39 (d, 1H), 8.18(d, 1H); MS (CI) 483 (MH⁺).,

Step E:1R-(4-{3R,5S-Dimethyl-4-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol.1R-(4-{3R,5S-dimethyl-4-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethylbutyrate (prepared according to the method of Example 208, Step D, 11.3g, 23.5 mmol) was combined with concentrated hydrochloric acid (60 mL)and stirred at ambient temperature for 4 h. The mixture was quenched insaturated aqueous sodium bicarbonate and extracted five times with 10%isopropanol/chloroform. The combined extracts were washed once withsaturated aqueous sodium chloride and the organic layer was dried oversodium sulfate and filtered. The filtrate was evaporated to an oil andcrystallized from isopropanol to give the title compound as a whitesolid, 7.34 g (76%). ¹H NMR (CDCl₃, 300 MHz) δ 1.21 (d, 6H), 1.51 (d,3H), 2.34 (s, 3H), 2.45 (m, 4H), 3.24 (m, 4H), 3.76 (m, 2H), 4.30-4.53(m, 4H), 4.68 (q, 1H), 5.82 (d, 1H), 6.42 (d, 1H), 7.94 (d, 1H), 8.21(d, 1H); mp: 181-182° C.; MS (CI) 413 (MH⁺).

Examples 209 to 211

Examples 209 to 211 were prepared from the appropriate startingmaterials in a manner analogous to the method of Example 208.

Ex- am- MS ple R¹¹ R⁷ R⁶ mp (° C.) (MH⁺) 209 2,6-dimethylmorpholin-3R-Me 5S-Me 428 4-yl 210 4-ethylpiperazin-1-yl 3R-Me 5S-Me 144-146 427211 4-isopropylpiperazin-1-yl 3R-Me 5S-Me 137-139 441

Example 212

1R-[4-[2R,6S-Dimethyl-4-(4-morpholino-4-yl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl]-ethanol.

Step A:1R-{4-[4-(4-Chloro-6-morpholino-[113.5]triazin-2-yl)-2R,6S-dimethylpiperazin-1-yl]-pyrimidin-2-yl}-ethylbutyrate. To a solution of1R-[4-(2R,6S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl butyrate(prepared according to the method of Preparation Four, 0.31 g, 1.0 mmol)and sodium bicarbonate (0.17 g, 2.0 mmol) in dimethylformamide (3 mL)was added 2,4-dichloro-6-morpholino-[1,3,5]triazine (0.24 g, 1.0 mmol;Chem. Pharm. Bull. 1997, 45, 291) and stirred at ambient temperature for2 hours. The mixture was diluted with ethyl acetate and washed twicewith water, once with saturated aqueous sodium chloride, and the organiclayer was dried over sodium sulfate and filtered. The filtrate wasconcentrated to an oil, which was purified by flash chromatography (99:1chloroform:methanol) to give the title compound of Example 212, Step Aas a white solid, 0.19 g (37%). ¹H NMR (CDCl₃, 300 MHz) δ 0.93 (t, 3H),1.23 {d, 6H), 1.53 (d, 3H), 1.66 (m, 2H), 2.37 (t, 2H), 3.16 (m, 2H),3.72-3.78 (m, 10H), 4.12-4.78 (m, 2H), 5.65 (q, 1H), 6.34 (d, 1H), 8.19(m, 2H); MS (CI) 505, 507 (MH⁺).

Step B:1R-{4-[2R,6S-Dimethyl-4-(4-morpholino-4-yl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.To a solution of1R-{4-[4-(4-chloro-6-morpholino-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethylbutyrate (prepared according to the method of Example 212, Step A, 0.15g, 0.35 mmol) in ethanol (10 mL) was added 10% palladium on carbon (0.75g, 500 wt %) and hydrogenated at 45-50 psi using a Parr apparatus for 12hours. The catalyst was filtered off and the filtrate was concentratedto an oil which was added to concentrated hydrochloric acid (2 mL) andstirred at ambient temperature for 6 hours. The mixture was diluted withchloroform and washed twice with water, once with saturated aqueoussodium chloride and the organic layer was dried over sodium sulfate andfiltered. The filtrate was concentrated to give the title compound as awhite solid, 0.47 g (40%). ¹H NMR (CDCl₃, 300 MHz) δ 1.23 (d, 6H), 1.53(d, 3H), 3.16 (m, 2H), 3.72-3.78 (m, 10H), 4.124.78 (m, 3H), 6.34 (d,1H), 8.19 (m, 2H); mp: 78-82° C.; MS (CI) 401 (MH⁺); [α]_(D) +15.1 (c1.0, MeOH).

Example 213

1R-{4-[4-(4-Methoxy-6-methyl-[1,3,5]triazin-2-yl)-3R,5S-dimethylpiperazin-1yl]-pyrimidin-2-yl}-ethanol.

Step A:1R-[4-[4-(4-Chloro-6-methyl-[1,3,5]triazin-2-yl)-3R,5S-dimethylpiperazin-1-yl]-pyrimidin-2-yl}-ethylbutyrate. To a solution of1R-[4-(3R,5S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl butyrate(prepared according to the method of Preparation Three, 1.47 g, 6.43mmol) and sodium bicarbonate (2.25 g, 26.8 mmol) in dimethylformamide(10 mL) was added 2,4-dichloro-6-methyl-[1,3,5]triazine (0.88 g, 5.3mmol; Monatsh. Chem. 1970, 101, 724) and stirred at ambient temperaturefor 2 h. The mixture was diluted with ethyl acetate (150 mL) and washedtwice with water, once with 10% aqueous CuSO₄, once with saturatedaqueous sodium chloride, and the organic layer was dried over sodiumsulfate and filtered. The filtrate was concentrated to give the titlecompound of Example 213, Step A as a tan solid, 2.12 g (91%). ¹H NMR(CDCl₃, 300 MHz) δ 0.93 (t, 3H), 1.23 (m, 6H), 1.54 (d, 2H), 1.66 (m,2H), 2.31 (s, 3H), 2.37 (m, 2H), 2.41 (s, 1H), 3.19 (m, 2H), 4.22-4.55(m, 2H), 4.91 (m, 2H), 5.65 (q, 1H), 6.40 (d, 1H), 8.20 (d, 1H); MS (CI)434, 436 (MH⁺).

Step B:1R-{4-[4-(4-Methoxy-6-methyl-[1,3,5]triazin-2-yl)-3R,5S-dimethylpiperazin-1-yl]-pyrimidin-2-yl}-ethanol.A solution of sodium methoxide in methanol was freshly prepared byallowing sodium metal (0.4 g, 17:3 mmol) to dissolve in methanol (40mL). To this mixture was added1R-{4-[4-(4-chloro-6-methyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethylbutyrate (prepared according to the method of Example 213, Step A, 1.5g, 3.46 mmol) which was stirred at ambient temperature for 16 h. Thereaction mixture was evaporated to an oil, diluted with chloroform andwashed twice with water, once with saturated aqueous sodium chloride,and the organic layer was dried over sodium sulfate and filtered. Thefiltrate was concentrated to a clear oil which was crystallized fromisopropyl ether to give the title compound, as a white solid, 0.85 g(72%). ¹H NMR (CDCl₃, 300 MHz) δ 1.23 (d, 6H), 1.48 (d, 3H), 2.36 (s,3H), 3.20-3.26 (m, 2H), 3.90 (s, 3H), 4.18-4.43 (m, 2H), 4.63 (m, 2H),4.68 (q, 1H), 4.85 (d, 1H), 6.42 (d, 1H), 8.18 (d, 1H); mp: 161-162° C.;MS (CI), 360 (MH⁺); [α]_(D) +16.8 (c 1.0, MeOH).

Example 214

1R-{4-[4-(4,6-Dimethoxy-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.

Step A:1R-{4-[4-(4,6-Dichloro-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethylbutyrate. To a solution of1R-[4-(3R,5S-Dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl butyrate(prepared according to the method of Preparation Three, 3.25 g, 10.5mmol) and sodium bicarbonate (1.01 g, 19.2 mmol) in dimethylformamide (8mL) was added cyanuric chloride (1.76 g, 9.6 mmol) and stirred atambient temperature for 2 h. The mixture was diluted with ethyl acetateand washed twice with water, once with saturated aqueous sodiumchloride, and the organic layer was dried over sodium sulfate andfiltered. The filtrate was concentrated to give the title compound ofExample 214, Step A as a white semi-solid, 1.42 g (68%). ¹H NMR (CDCl₃,300 MHz) δ 0.93 (t, 3H), 1.23 (m, 6H), 1.54 (d, 3H), 1.66 (m, 2H), 2.37(m, 2H), 3.19 (m, 2H), 4.42-4.55 (m, 2H), 4.91 (m, 2H), 5.65 (q, 1H),6.40 (d, 1H), 8.20 (d, 1H); MS (CI) 446, 448 (MH⁺).

Step B:1R-[4-[4-(4,6-Dimethoxy-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl]-ethanol.A solution of sodium methoxide in methanol was freshly prepared byallowing sodium metal (0.18 g, 8.0 mmol) to dissolve in methanol (16mL). To this mixture was added1R-{4-[4-(4,6-dichloro-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethylbutyrate (prepared according to the, method of Example 214, Step A, 0.91g, 2.0 mmol) at 0° C., then warmed to ambient temperature for 1 h. Themixture was evaporated to an oil, diluted with chloroform and washedonce with water, once with saturated aqueous sodium chloride, dried oversodium sulfate and filtered. The filtrate was concentrated to a clearoil which crystallized from isopropyl ether to give the title compoundas a white solid, 0.54 g (72%). ¹H NMR (CDCl₃, 300 MHz) δ 1.23 (d, 6H),1.50 (d, 3H), 3.20 (m, 2H), 3.95 (s, 6H), 4.32 (m, 1H), 4.67-4.86 (m,4H), 6.34 (d, 1H), 8.22 (d, 1H); mp: 187-188° C.; MS (CI) 376 (MH⁺).

Example 215

1R-[2R,6S-Dimethyl-4-(4-phenyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl]ethanol.

Step A:1R-{4-[4-(4-Chloro-6-phenyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethylbutyrate. To a solution of1R-[4-(2R,6S-dimethyl-piperazin-1-yl)-pyrmidin-2-yl]-ethyl butyrate(prepared according to the method of Preparation Four, 2.35 g, 7.67mmol) and sodium bicarbonate (1.29 g, 15.3 mmol) in dimethylformamide(25 mL) at 0° C. was added 2,4-dichloro-6-phenyl[1,3,5]triazine (1.73 g,7.67 mmol; Helv. Chim. Acta 1950, 33, 1365) portionwise. The reactionmixture was allowed to warm to room temperature and stir under nitrogenfor 4 h, poured into water then filtered to give the title compound ofExample 215, Step A as a light tan solid, 1.99 g (51%). ¹H NMR (CDCl₃,400 MHz) δ 0.94 (t, 3H), 1.25 (d, 6H), 1.57 (d, 3H), 1.68 (m, 2H), 2.40(t, 2H), 3.27 (d, 2H), 4.65 (m, 2H), 4.82 (d, 1H), 5.00 (d, 1H), 5.68(q, 1H), 6.34 (d, 1H), 7.46 (m, 3H), 8.21 (d, 1H), 8.40 (d, 2H); MS (CI)496, 498 (MH⁺).

Step B:1R-{4-[4-(6-phenyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethylbutyrate. To a solution of1R-{4-[4-(4-chloro-6-phenyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethylbutyrate (prepared according to the method of Example 215, Step A, 4.81g, 9.7 mmol) in methanol (50 mL) was added 10% palladium on carbon (940mg, 20 wt %), ammonium formate (5.98 g, 97 mmol), and hydrochloric acid(2 M in ethyl ether, 7.1 mL, 14.2 mmol) and refluxed for 1.5 h. Themixture was allowed to cool, then filtered. The filtrate wasconcentrated and partitioned between chloroform and saturated aqueoussodium bicarbonate. The organic layer was separated, dried over sodiumsulfate, filtered, and the filtrate was evaporated to an oil which waspurified by flash chromatography (99:1 chloroform:methanol) to give thetitle compound of Example 215, Step B as a clear oil, 2.69 g (59%). ¹HNMR (CDCl₃, 400 MHz) δ 0.95 (t, 3H), 1.25 (d, 6H), 1.57 (d, 3H), 1.68(m, 2H), 2.40 (t, 2H), 3.27 (d, 2H), 4.65 (m, 2H), 4.82 (d, 1H), 5.00(d, 1H), 5.68 (q, 1H), 6.34 (d, 1H), 7.46 (m, 3H), 8.21 (d, 1H), 8.40(d, 2H), 8.66 (s, 1H); MS (CI) 462 (MH⁺).

Step C:1R-{2R,6S-Dimethyl-4-(4-phenyl-[1,3,5]triazin-2-yl)-piperazin-1-yl}-pyrimidin-2-yl}-ethanol.Concentrated hydrochloric acid (10 mL) was added to1R-{4-[4-(6-phenyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1yl]-pyrimidin-2-yl}-ethyl butyrate (prepared according to the method ofExample 215, Step B, 2.69 g, 5.8 mmol) and allowed to stir for 5 h atambient temperature. The reaction mixture was cooled to 0° C., dilutedwith chloroform, and 6 M aqueous sodium hydroxide was added slowly untilbasic (pH 9). The layers were separated and the aqueous layer wasextracted twice with chloroform. The combined organic extracts werewashed once with saturated aqueous sodium chloride, dried over sodiumsulfate, filtered, and the filtrate was concentrated to an oil which waspurified by flash chromatography (97:3 chloroform:methanol) to give awhite foam that crystallized from isopropyl ether to give the titlecompound as a white solid, 1.55 g (68%). ¹H NMR (CDCl₃, 400 MHz) δ 1.28(d, 6H), 1.54 (d, 3H), 3.31 (d, 2H), 4.63 (m, 2H), 4.77 (q, 1H), 4.85(d, 1H), 5.50 (d, 1H), 6.42 (d, 1H), 7.50 (m, 3H), 8.25 (d, 1H), 8.41(d, 2H), 8.68 (s, 1H); mp: 133-134° C.; MS (CI) 392 (MH⁺); [α]_(D) +18.7(c 1.07, MeOH).

Examples 216 to 235

Examples 216 to 235 were prepared from the appropriate startingmaterials in a manner analogous to the method of Example 215.

Example R¹¹ R¹² R⁶ R⁷ mp (° C.) MS (MH⁺) 216 Cl morpholin-4-yl 2R-Me6S-Me 138-141 435, 437 217 H morpholin-4-yl 3R-Me 5S-Me 152 401 218 OMemorpholin-4-yl 2R-Me 6S-Me 176-178 431 219 Me 4-methyl-piperazin-1-yl3R-Me 5S-Me 428 220 Me H 2R-Me 6S-Me 91-94 330 221 OMe OMe 2R-Me 6S-Me128-129 376 222 OEt Me 3R-Me 5S-Me 141-142 374 223 OiPr Me 3R-Me 5S-Me87-91 388 224 phenyl H 3R-Me 5S-Me 154-155 392 225 phenyl OMe 3R-Me5S-Me 422 226 phenyl OMe 2R-Me 6S-Me 135-138 422 227 iPr H 2R-Me 6S-Me122-124 358 228 iPr OMe 3R-Me 5S-Me 75-80 388 229 phenyl H H H 115-117364 230 OMe Me H H 173-175 332 231 o-tolyl H 3R-Me 5S-Me 123-125 406 232o-tolyl OMe 3R-Me 5S-Me 143-145 436 233 cyclopropyl H 3R-Me 5S-Me134-135 356 234 cyclopropyl H 2R-Me 6S-Me 133-134 356 235 OMe CH₂OMe3R-Me 5S-Me 104-105 390

Example 236

1R-{4-[4-(4-Hydroxymethyl-6-methoxy-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.

Step A:1R-{4-[4-(4-Chloro-6-diazomethyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethylbutyrate. To a solution of1R-[4-(3R,5S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl butyrate(prepared according to the method of Preparation Three, 3.06 g, 10.0mmol) and sodium bicarbonate (1.68 g, 20.0 mmol) in dimethylformamide(10, mL) was added 2,4-dichloro-6-diazomethyl-[1,3,5]triazine (1.90 g,10.0 mmol; J. Am. Chem. Soc. 1957, 79, 944) and stirred at ambienttemperature for 2 h. The mixture was diluted with ethyl acetate, washedtwice with water, once with saturated aqueous sodium chloride, and theorganic layer was dried over sodium sulfate and filtered. The filtratewas concentrated and purified by flash chromatography (ethyl acetate) togive the title compound of Example 236, Step A as a foam, 1.84 g (41%).¹H NMR (CDCl₃, 300 MHz) δ 0.94 (t, 3H), 1.23 (m, 6H), 1.55 (d, 3H), 1.66(m, 2H), 2.38 (m, 2H), 3.19 (m, 2H), 4.22-4.45 (m, 2H), 4.86 (m, 2H),5.10 (s, 1H), 5.65 (q, 1H), 6.40 (d, 1H), 8.20 (d, 1H); mp: 106-108° C.;MS (CI) 461, 463 (MH⁺).

Step B:1R-{4-[4-(4-Hydroxymethyl-6-methoxy-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.1R-{4-[4-(4-Chloro-6-diazomethyl-[1,3,5]triazin-2-yl)-3R,5S-dimethylpiperazin-1-yl]-pyrimidin-2-yl}-ethylbutyrate (prepared according to the method of Example 236, Step A, 1.5g, 3.2 mmol) was dissolved in ethyl acetate (20 mL) and 10% aqueoussulfuric acid (5 mL) was added slowly at ambient temperature, stirred 5min then basified to pH 9 with 6 N aqueous sodium hydroxide. Theseparated ethyl acetate layer was washed once with brine, dried overmagnesium sulfate, and concentrated to a semi-solid. To a freshlyprepared solution of sodium methoxide, generated by dissolving sodiummetal (0.92 g, 4.0 mmol) in methanol (6 mL), was added the crude solid(0.89 g, 2.0 mmol). This mixture was stirred for 4 h at ambienttemperature then evaporated to dryness. The residue was purified byflash chromatography (95:5 dichloromethane:methanol) to give the titlecompound as a white solid, 0.084 g (13%). ¹H NMR (CDCl₃, 300 MHz) δ 1.23(d, 6H), 1.49 (d, 3H), 3.14-3.21 (m, 2H), 3.96 (m, 2H), 3.90 (s, 3H),41.18-4.38 (m, 2H), 4.69 (q, 1H), 4.97 (m, 2H), 6.44 (d, 1H), 8.20 (d,1H); mp: 170-171° C.; MS (CI) 376 (MH⁺); [α]_(D) +16.6 (c 1.0, MeOH).

Example 237

1R-{4-[4-(4-Methoxymethyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl-pyrimidin-2-yl]-ethanol.

Step A:1R-[4-[4-(4-Chloro-6-methoxymethyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethylbutyrate.1R-{4-[4-(4-Chloro-6-diazomethyl-[1,3,5]triazin-2-yl)-3R,5S-dimethylpiperazin-1-yl]-pyrimidin-2-yl}-ethylbutyrate (prepared according to the method of Example 236, Step A, 1.5g, 3.2 mmol) was dissolved in methanol (10 mL) and 10% aqueous sulfuricacid (3 mL) was added. This mixture was stirred at ambient temperaturefor 1 h then diluted with ethyl acetate. The separated ethyl acetatelayer was washed once with saturated aqueous sodium chloride, dried overmagnesium sulfate, and concentrated to an oil which was purified byflash chromatography (99:1 dichloromethane:methanol) to give the titlecompound of Example 237, Step A as an oil, 1.02 (60%). ¹H NMR (CDCl₃,300 MHz) δ 0.95 (t, 3H), 1.26 (d, 6H), 1.58 (d, 3H), 1.67 (q, 2H), 2.41(t, 2H), 3.24 (m, 2H), 3.51 (s, 3H), 4.184.38 (m, 4H), 4.69 (q, 1H),4.92 (m, 2H), 6.47 (d, 1H), 8.24 (d, 1H); MS (CI) 464, 466 (MH⁺).

Step B:1R-{4-[4-(4-Methoxymethyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.To a solution of1R-{4-[4-(4-chloro-6-methoxymethyl-[1,3,5]triazin-2-yl)-3R,5S-dimethpiperazin-1-yl]-pyrimidin-2-yl}-ethylbutyrate (prepared according to the method of Example 237, Step A, 0.43g, 0.92 mmol) in methanol (8 mL) and hydrochloric acid (2 M in ethylether, 0.7 mL, 1.37 mmol) was added ammonium formate (0.58 g, 9.2 mmol)and 10% palladium on carbon (0.085 g, 20 wt %) and heated to reflux for3 h. The solvents were removed and concentrated hydrochloric acid (2 mL)was added and stirred at ambient temperature for 16 h, basified to pH 9with 6 N aqueous sodium hydroxide and diluted with ethyl acetate. Theseparated ethyl acetate layer was washed once with saturated aqueoussodium chloride, dried over magnesiumsulfate, and concentrated to an oilwhich was purified by flash chromatography (9:1dichloromethane:methanol) to give the title compound as a white solid,0.12 g (36%). ¹H NMR (CDCl₃, 300 MHz) δ 1.25 (d, 6H), 1.49, (d, 3H),3.24 (m, 2H), 3.51 (s, 3H), 4.18-4.38 (m, 4H), 4.72 (q, 1H), 4.97 (m,2H), 6.47 (d, 1H), 8.22 (d, 1H), 8.57 (s, 1H); MS (Cl) 360 (MH⁺).

Examples 238 to 240

Examples 238 to 240 were prepared from the appropriate startingmaterials in a manner analogous to the method of Example 237.

Exam- ple R¹¹ R¹² R⁷ R⁶ mp (° C.) MS (MH⁺) 238 CH₂OH H 3R-Me 5S-Me173-175 346 239 OMe CH₂OMe 3R-Me 5S-Me 143-145 390 240 CH₂OH phenyl2R-Me 6S-Me 173-175 422

Example 241

1R-{4-[4-(4,6-Dimethyl-[1,3,5]triazin-2-yl)-2R,6S-dimethylpiperazin-1-yl]-pyrimidin-2-yl}-ethanol.

Step A:1R-{4-[4-(4-Methyl-6-trichloromethyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethylbutyrate. To a solution of1R-[4-(2R,6S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl butyratedibenzoyl-L-tartrate salt (prepared according to the method ofPreparation Fifteen, 1.33 g, 2.0 mmol) and sodium bicarbonate (0.34 g,4.0 mmol) in dimethylformamide (5 mL) was added2-methyl-4,6-bis-trichloromethyl-[1,3,5]triazine (1.00 g, 3.0 mmol;Bull. Chem. Soc., Jpn. 1969, 42, 2924) and stirred at ambienttemperature for 14 h. The mixture was diluted with ethyl acetate andwashed twice with water and the organic layer was dried over magnesiumsulfate and concentrated. The crude oil was purified by flashchromatography (95:5 dichloromethane:methanol) to give the titlecompound of Example 241, Step A as a foam, 0.71 g (69%). ¹H NMR (CDCl₃,300 MHz) δ 0.95 (t, 3H), 1.22 (m, 6H), 1.56 (d, 3H), 1.66 (m, 2H), 2.37(m, 2H), 2.55 (s, 1H), 3.27 (m, 2H), 4.48-4.78 (m, 2H), 4.84 (m, 2H),5.67 (q, 1H), 6.32 (d, 1H), 8.22 (d, 1H); MS (CI) 517, 519 (MH⁺).

Step B:1R-{4-[4-(4,6-Dimethyl-[1,3,5]triazin-2-yl)-2R,6S-dimethylpiperazin-1-yl]-pyrimidin-2-yl}-ethanol.A suspension of1R-{4-[4-(4-methyl-6-trichloromethyl-[1,3,5]triazin-2-yl)-2R,6S dimethylpiperazin-1-yl]-pyrimidin-2-yl}-ethyl butyrate (prepared according tothe method of Example 241, Step A, 0.65 g, 1.2 mmol) and 10% palladiumon carbon (0.2 g) in triethylamine (1 mL) and methanol (20 mL) washydrogenated at 40 psi for 0.5 hours using a Parr apparatus. Thecatalyst was filtered and the filtrate was concentrated to a solid whichwas dissolved in concentrated hydrochloric acid (2 mL) and stirred for 6hours. This mixture was diluted with water, basified to pH 9 with 6 Naqueous sodium hydroxide, and extracted into dichloromethane. Theextract was washed twice with water, once with saturated aqueous sodiumchloride and the organic layer was dried over sodium sulfate andfiltered. The filtrate was concentrated to a clear oil whichcrystallized from isopropyl ether to give the title compound as a whitesolid, 0.25 g (58%). ¹H NMR (CDCl₃, 300 MHz) δ 1.21 (d, 6H), 1.49 (d,3H), 2.40 (s, 6H), 3.16 (m, 2H), 4.45-4.68 (m, 2H), 4.71 (q, 1H), 4.84(m, 2H), 6.42 (d, 1H), 8.20 (d, 1H); mp: 172-173° C.; MS (CI) 344 (MH⁺);[α]_(D) +17.2 (c 1.0, MeOH).

Example 242

1R-{4-[4-(4,6-Dimethyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.,

Step A: 4-Methyl-6-trichloromethyl-f 1.3.5]triazin-2-ylmethanesulfonate. To a solution of2-hydroxy-4-methyl-6-trichloromethyl-[1,3,5]triazine (1.14 g, 5.0 mmol;J. Amer. Chem. Soc. 1956, 178, 2447) and triethylamine (0.51 g, 5.5mmol) in dichloromethane was added methanesulfonyl chloride (0.57 g, 5.0mmol) at 0° C. and stirred for 1 h then quenched in saturated aqueoussodium bicarbonate. The separated organic layer was washed once withsaturated sodium chloride, dried over magnesium sulfate and filtered.The filtrate was evaporated to give the title compound of Example 242,Step A as an orange oil, 0.98 g (65%) which was used directly withoutany further purification. MS (CI) 291, 293 (MH⁺).

Step B:1R-{4-[3R,5S-Dimethyl-4-(4-methyl-6-trichloromethyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-pyrmidin-2-yl}-ethylbutyrate. To a solution of1R-[4-(3R,5S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl butyrate(prepared according to the method of Preparation Three, 0.62 g, 2.0mmol) and sodium bicarbonate (0.34 g, 4.0 mmol) in dimethylformamide (5mL) was added 4-methyl-6-trichloromethyl-[1,3,5]triazin-2-ylmethanesulfonate (prepared according to the method of Example 242, StepA, 1.00 g, 3.0 mmol) and stirred at ambient temperature for 14 h. Themixture was diluted with ethyl acetate and washed twice with water andthe organic layer was dried over magnesium sulfate and concentrated. Thecrude oil was purified by flash chromatography (ethyl acetate) to givethe title compound of Example 242, Step B as a clear oil, 0.41 mg (96%).¹H NMR (CDCl₃, 300 MHz) δ 0.95 (t, 3H), 1.22 (m, 6H), 1.56 (d, 3H), 1.66(m, 2H), 2.37 (m, 2H), 2.55 (s, 3H), 3.27 (m, 2H), 4.484.78 (m, 2H),4.84 (m, 2H), 5.67 (q, 1H), 6.32 (d, 1H), 8.22 (d, 1H); MS (CI) 517, 519(MH⁺).

Step C:1R-{4-[4-(4,6-Dimethyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.A suspension of1R-{4-[3R,5S-dimethyl-4-(4-methyl-6-trichloromethyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethylbutyrate (prepared according to the method of Example 242, Step B, 0.65g, 1.2 mmol) and 10% palladium on carbon (0.2 g, 30 wt %) intriethylamine (1 mL) and methanol (20 mL) was hydrogenated at 40 psi for0.5 h using a Parr, apparatus. The catalyst was filtered off and thefiltrate was concentrated to a solid which was dissolved in concentratedhydrochloric acid (3 mL) and stirred for 6 h. This mixture was dilutedwith water, basified to pH 9 with 6 N aqueous sodium hydroxide, andextracted into dichloromethane. The extract was washed twice with waterand once with saturated aqueous sodium chloride and the organic layerwas dried over sodium sulfate and concentrated to a clear oil whichcrystallized from isopropyl ether to give the title compound as a whitesolid, 0.25 g (23%). ¹H NMR (CDCl₃, 300 MHz) δ 1.21 (d, 6H), 1.49 (d,3H), 2.40 (s, 6H), 3.16 (m, 2H), 4.45-4.68 (m, 2H), 4.71 (q, 1H), 6.42(d, 1H), 8.20 (d, 1H) MS (CI) 344 (MH⁺); mp: 157-159° C.; [α]_(D) +17.2(c 1.0, MeOH).

Examples 243 to 246

Examples 243 to 246 were prepared from the appropriate startingmaterials in a manner analogous to the method of Example 242.

Ex- am- MS ple R¹¹ R¹² R⁷ R⁶ mp (° C.) (MH⁺) 243 Me phenyl 2R-Me 6S-Me406 244 Me phenyl 3R-Me 5S-Me 132-134 406 245 Me tetrahydrofuran- 2R-Me6S-Me 428 2-yl 246 Me O-tolyl 2R-Me 6S-Me 148-150 436

Example 247

(R)-2-[2-(1-Hydroxy-ethyl)-pyrimidin-4-yl]-1,2,3,4-tetrahydro-isoquinoline-7-sulfonic,acid dimethylamide.

Step A: 2-Trifluorcacetyl-1,2,3,4-tetrahydro-isoquinoline-7-sulfonicacid dimethylamide. A mixture of2-trifluoroacetyl-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl chloride(400 mg, 1.22 mmol, J. Med. Chem. 1980, 23, 837), dimethylaminehydrochloride (150 mg, 1.83 mmol), and triethylamine (0.50 mL, 3.66mmol) in dioxane (10 mL) was refluxed with stirring for 30 min, cooledto room temperature, concentrated, and purified by flash columnchromatography (10→50% ethyl acetate/hexanes) to give 337 mg (82%) ofthe title compound of Example 247, Step A as a yellow oil. ¹H NMR(CDCl₃, 300 MHz, 9:5 mixture of rotamers) δ 7.67-7.52 (c, 2H), 7.36 (t,1H), 4.87 (s, 1.3H), 4.81 (s, 0.7H), 3.96-3.86 (c, 2H), 3.08-3.02 (c,2H), 2.72 (s, 6H); MS (TS) 337 (MH⁺).

Step B: 1,2,3,4-Tetrahydro-isoquinoline-7-sulfonic acid dimethylamide. Amixture of 2-trifluoroacetyl-1,2,3,4-tetrahydro-isoquinoline-7-sulfonicacid dimethylamide (prepared according to the method of Example 247,Step A, 337 mg, 1.0 mmol) and potassium carbonate (207 mg, 1.5 mmol) ina 3:1 mixture of methanol/water (10 mL) was stirred at room temperaturefor 1 h and concentrated. The remaining aqueous residue was extractedwith 10% isopropanol/chloroform (7×) and the combined organic extractswere dried over sodium sulfate, filtered, and evaporated to give 214 mg(89%) of the title compound of Example 247, Step B as a white solid. ¹HNMR (CD₃OD, 300 MHz) δ 7.52 (d, 1H), 7.48 (s, 1H), 7.36 (d, 1H), 4.90(s, 2H), 3.11 (t, 2H), 2.91 (t, 2H), 2.65 (s, 6H); MS (CI/NH₃) 241(MH⁺).

Step C:(R)-1-[4-(7-Dimethylsulfamoyl-3,4-dihydro-1H-isoquinolin-2-yl)-pyrimidin-2-yl]-ethylacetate. To a solution of 1,2,3,4-tetrahydro-isoquinoline-7-sulfonicacid dimethylamide (prepared according to the method of Example 247,Step B, 210 mg, 0.88 mmol) in isopropanol (5 mL) was added(R)-1-(4-chloro-pyrimidin-2-yl)-ethyl acetate (prepared according to themethod of Preparation Five, 175 mg, 0.88 mmol) followed by triethylamine(0.24 mL, 1.75 mmol). This mixture was stirred at room temperature for1.75 h then heated to reflux for 1.5 h, cooled to room temperature,evaporated, and purified by flash column chromatography (1%methanol/chloroform) to give 327 mg, (92%) of the title compound ofExample 247, Step C as a white solid. ¹H NMR (CDCl₃, 250 MHz) δ 8.28 (d,1H), 7.68-7.58 (c, 2H), 7.47 (d, 1H), 6.44 (d, 1H), 5.72 (q, 1H), 4.86(s, 2H), 3.92 (t, 2H), 3.05 (t, 2H), 2.73 (s, 6H), 2.19 (s, 3H), 1.62(d, 3H); MS (TS), 431 (MH⁺).

Step D:(R)-2-[2-(1-Hydroxy-ethyl)-pyrimidin-4-yl]-1,2,3,4-tetrahydro-isoquinoline-7-sulfonicacid dimethylamide. To a solution of(R)-1-[4-(7-dimethylsulfamoyl-3,4-dihydro-1H-isoquinolin-2-yl)-pyrimidin-2-yl]-ethylacetate (prepared according to the method of Example 247, Step C, 326mg, 0.81 mmol) in a 4:1 mixture of methanol/water (8 mL) was addedlithium hydroxide hydrate (170 mg, 4.0 mmol). This mixture was stirredat room temperature for 50 min, concentrated, re-suspended in water andextracted with 10% isopropanol/chloroform (3×). The combined organicextracts were dried over sodium sulfate, filtered, evaporated, andpurified by flash column chromatography (1% methanol/chloroform) to givea white foam which was further purified by recrystallization fromether/methanol to give 90 mg (31%) of the title compound as a whitesolid. mp: 120.5-122° C.; ¹H NMR (CDCl₃, 300 MHz) δ 8.24 (d, 1H),7.62-7.59 (c, 2H), 7.35 (d, 1H), 6.44 (d, 1H), 4.83 (s, 2H), 4.73 (q,1H), 4.34 (br s, 1H), 3.93-3.85 (c, 2H), 3.03 (t, 2H), 2.71 (s, 6H),1.52 (d, 3H); MS (TS) 363 (MH⁺).

Example 248

1-[4-(6-Thiophen-3-yl-3,4-dihydro-1H-isoquinolin-2-yl)-pyrimidin-2-yl]-ethanol.

Step A: 6-Thiophen-3-yl-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester. A mixture of bis(benzonitrile)palladium(II) chloride(30 mg, 0.079 mmol) and 1,4-bis(diphenylphosphino)butane (33.6 mg, 0.079mmol) in toluene (3 mL) was stirred at room temperature for 20 min. Tothis mixture was added6-trifluoromethanesulfonyloxy-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (300 mg, 0.79 mmol, Synth. Commun. 1995, 25,3255), thiophene-3-boronic acid (131 mg, 1.02 mmol), 1 M aqueous sodiumcarbonate (1.57 mL, 1.57 mmol), and ethanol (2 mL). This dark mixturewas heated to reflux with stirring under nitrogen overnight, cooled toroom temperature, diluted with saturated aqueous sodium bicarbonate, andextracted with ethyl acetate (4×). The combined organic extracts weredried over sodium sulfate, filtered through Celite, evaporated, andpurified by flash column chromatography (hexanes-5% ethylacetate/hexanes) to give 252 mg (100%) of the title compound of Example248, Step A as a pale yellow waxy solid. ¹H NMR (CDCl₃, 250 MHz) δ7.47-7.38 (c, 5H), 7.14 (d, 1H), 4.60 (s, 2H), 3.72-3.64 (c, 2H),2.95-2.82 (c, 2H), 1.52 (s, 9H); MS (TS) 316 (MH⁺).

Step B: 6-Thiophen-3-yl-3,4-dihydro-1H-isoquinoline hydrochloride. Amixture of 6-(thiophen-3-yl-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (prepared according to the method of Example 248,Step A, 250 mg, 0.79 mmol) and hydrochloric acid (4 M in dioxane, 6 mL,23.8 mmol) was stirred at room temperature for 1 h and concentrated togive 170 mg (86%) of the title compound of Example 248, Step B as ayellow solid that was used without purification in the next step. ¹H NMR(CD₃OD, 250 MHz) δ 7.66 (m, 1H), 7.61-7.53 (c, 2H), 7.51-7.42 (c, 2H),7.23 (d, 2H), 4.38 (s, 2H), 3.52 (t, 2H), 3.16 (t, 2H); MS (TS) 216(MH⁺).

Step C:(R)-1-[4-(6-Thiophen-3-yl-3,4-dihydro-1H-isoquinolin-2-yl)-pyrimidin-2-yl]-,ethyl acetate. To a solution of6-thiophen-3-yl-3,4-dihydro-1H-isoquinoline hydrochloride (preparedaccording to the method of Example 248, Step B, 170 mg, 0.68 mmol) inisopropanol (6 mL) was added (R)-1-(4-chloro-pyrimidin-2-yl)-ethylacetate (prepared according to the method of Preparation Five, 136 mg,0.68 mmol) followed by triethylamine (0.28 mL, 2.04 mmol). This mixturewas stirred at reflux for 7 h, cooled to room temperature overnight,evaporated, and purified by flash column chromatography (0.51%methanol/chloroform) to give 253 mg (98%) of the title compound ofExample 248, Step C as a yellow solid. ¹H NMR (CDCl₃, 250 MHz) δ 8.26(d, 1H), 7.52-7.36 (c, 6H), 6.43 (d, 1H), 5.73 (q, 1H), 4.76 (s, 2H),3.96-3.82 (c, 2H), 3.02 (t, 2H), 2.21 (s, 3H), 1.63 (d, 3H); MS (TS) 380(MH⁺).

Step D:1-[4-(6-Thiophen-3-yl-3,4-dihydro-1H-isoquinolin-2-yl)-pyrimidin-2-yl]-ethanol.

To a solution of(R)-1-[4-(6-thiophen-3-yl-3,4-dihydro-1H-isoquinolin-2-yl)-pyrimidin-2-yl]-ethylacetate (prepared according to the method of Example 248, Step C, 253mg, 0.67 mmol) in a 3:1:1 mixture of methanol/tetrahydrofuran/water (5mL) was added lithium hydroxide hydrate (84 mg, 2.0 mmol). This mixturewas stirred at room temperature for 1 h, concentrated, re-suspended inwater, and extracted with chloroform (4×). The combined organic extractswere dried over sodium sulfate, filtered, evaporated, and purified byflash column chromatography (2% methanol/chloroform) to give a yellowsolid which was further purified by recrystallization, fromether/methanol to give 163 mg (72%) of the title compound as a whitesolid. mp: 125.5-127.5° C.; ¹H NMR (CDCl₃, 360 MHz) δ 8.22 (d, 1H),7.47-7.35 (c, 5H), 7.22 (d, 1H), 6.42 (d, 1H), 4.78-4.72 (c, 2H), 4.46(br s, 1H), 3.93-3.84 (c, 2H), 2.99 (t, 2H), 1.54 (d, 3H); MS (APCI) 338(MH⁺).

Examples 249 to 252

Examples 249 to 252 were prepared from the appropriate startingmaterials in a manner analogous, to the method of Example 248.

Example R²⁸ mp (° C.) MS (MH⁺) 249 6-thiophen-2-yl 104-105 338 2506-pyrimidin-5-yl 334 251 7-pyrimidin-5-yl 135-137 334 252 6-hydroxy 272

Examples 253 to 258

Examples 253 to 258 were prepared from the appropriate startingmaterials in a manner analogous to the method of Example 86.

Example R²⁸ mp (° C.) MS (MH⁺) 253 H 79-82 258 254 Me 272 255 CF₃130-132 326 256 NH₂ 208-210 273 257 Ph 128-131 334 258 pyridin-4-yl144-148 335

Example 259

(R)-1-[4-(3-Benzothiazol-2-yl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-pyrimidin-2-yl]-ethanol.

Step A: 5-Ethoxy-3,6-dihydro-2H-pyrazine-1-carboxylic acid benzyl ester.To a solution of 3-oxo-piperazine-1-carboxylic acid benzyl ester (2.0 g,8.54 mmol, Maybridge) in dichloromethane (18 mL) at room temperature wasadded triethyloxonium tetrafluoroborate (4.1 g, 21.3 mmol). This mixturewas allowed to stir for about 3 days then quenched by the addition ofice chips followed by saturated aqueous sodium bicarbonate until aneutral pH was obtained. The organic layer was separated and the aqueouslayer was extracted with chloroform (3×). The combined organic extractswere washed with brine (1×), dried over sodium sulfate, and concentratedto give 2.11 g (95%) of the title compound of Example 259, Step A as aslightly yellow oil that was sufficiently pure to carry on to the nextstep. ¹H NMR (CDCl₃, 300 MHz) δ 7.43-6.97 (c, 5H), 5.17 (s, 2H), 4.10(q, 2H), 3.98 (s, 2H), 3.60-3.40 (c, 4H), 1.27 (t, 3H); MS (APCI) 263(MH⁺).

Step B:3-Benzothiazol-2-yl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine-7-carboxylicacid benzyl ester. A mixture of5-ethoxy-3,6-dihydro-2H-pyrazine-1-carboxylic acid benzyl ester(prepared according to the method of Example 259, Step A, 490 mg, 1.87mmol) and benzothiazole-2-carboxylic acid hydrazide (360 mg, 1.87 mmol;J. Org. Chem. 1958, 23, 1344) in n-butanol (2 mL) was stirred at refluxovernight, cooled to room temperature, concentrated, and purified byflash column chromatography (1% methanol/chloroform) to give 580 mg ofthe title compound of Example 259, Step B (contaminated with anequimolar amount of benzothiazole-2-carboxylic acid hydrazide which wasremoved in the subsequent step) as a yellow solid.

Step C:3-Benzothiazol-2-yl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine. To asolution of3-benzothiazol-2-yl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine-7-carboxylicacid benzyl ester (prepared according to the method of Example 259, StepB, 580 mg, contaminated with benzothiazole-2-carboxylic acid hydrazide)in dichloromethane (10 mL) at 0° C. was added a solution of borontribromide (1 M in dichloromethane, 4.45 mL, 4.45 mmol). This mixturewas warmed to room temperature overnight, quenched by addition of water,and concentrated. The residual aqueous layer was washed with ether (6×),neutralized with saturated aqueous sodium bicarbonate, and extractedwith 10% isopropanol/chloroform (3×). The combined organic extracts weredried over sodium sulfate, filtered, evaporated, and purified by flashcolumn chromatography (110% methanol/chloroform) to give 175 mg (36%,two steps) of the title compound of Example 259, Step C as a whitesolid. ¹H NMR (CDCl₃, 300 MHz) δ 8.05 (d, 1H), 7.96 (d, 1H), 7.57-7.41(c, 2H), 4.62 (t, 2H), 4.36 (s, 2H), 3.35 (t, 2H); MS (APCI) 258 (MH⁺).

Step D:(R)-1-[4-(3-Benzothiazol-2-yl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-pyrimidin-2-yl]-ethylbutyrate. A mixture of3-benzothiazol-2-yl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine(prepared according to the method of Example 259, Step C, 170 mg, 0.66mmol), (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (preparedaccording to the method of Preparation Seven, 150 mg, 0.66 mmol), andtriethylamine (0.28 mL, 1.98 mmol) in n-butanol (2.2 mL) was heated toreflux overnight, cooled to room temperature, evaporated, and purifiedby flash column chromatography (1% methanol/chloroform) to give 224 mg(76%) of the title compound of Example 259, Step D as a colorless solid.¹H NMR (CDCl₃, 300 MHz) δ 8.37 (d, 1H), 8.08 (d, 1H), 7.97 (d, 1H),7.57-7.43 (c, 2H), 6.53 (d, 1H), 5.711 (q, 1H), 5.09 (s, 2H), 4.82 (t,2H), 4.33-4.26 (c, 2H), 2.42 (t, 2H), 1.78-1.64 (c, 2H), 1.61 (d, 3H),0.99 (t, 3H); MS (APCI) 450 (MH⁺).

Step E:(R)-1-[4-(3-Benzothiazol-2-yl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-pyrimidin-2-yl]-ethanol.To a solution of(R)-1-[4-(3-benzothiazol-2-yl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-pyrimidin-2-yl]-ethylbutyrate (prepared according to the method of Example 259, Step D, 220mg, 0.49 mmol) in a 3:1:1 mixture of tetrahydrofuran/methanol/water (5mL) was added lithium hydroxide hydrate (62 mg, 1.47 mmol). This mixturewas stirred at room temperature for 3 h, concentrated, and extractedwith chloroform (3×). The combined organic extracts were dried oversodium sulfate, filtered, evaporated, and purified, by flash columnchromatography (5% methanol/chloroform) to give 192 mg (100%) of thetitle compound as a colorless solid. mp: 216.5-218.5° C.; ¹H NMR (CDCl₃,300 MHz) δ 8.37 (d, 1H), 8.06 (d, 1H), 7.97 (d, 1H), 7.56-7.45 (c, 2H),6.56 (d, 1H), 5.11 (s, 2H), 4.83 (t, 2H), 4.77 (m, 1H), 4.35-4.25 (c,2H), 4.16 (s, 1H), 1.54 (d, 3H); MS (APCI) 380 (MH⁺), [α]_(D) +14.2 (c1.0, CHCl₃).

Examples 260 to 263

Examples 260 to 263 were prepared from the appropriate startingmaterials in a manner analogous to the method of Example 259.

Example R³³ mp (° C.) MS (MH⁺) 260 phenyl 161-164 323 261quinoxalin-6-yl 212-215 375 262 benzothiophen-2-yl 224-226 379 263biphen-4-yl 123-125 399

Example 264

(R)-1-[4-(Spiro[benzothiazoline-2,4′-piperidine])-pyrimidin-2-yl]-ethanol.

Step A: Spiro[benzothiazolin-2,4′-piperidine]hydrochloride. To asolution of 1′-benzylspiro[benzothiazoline-2,4′-piperidine] (500 mg,1.69 mmol; Indian J. Chem. 1976, 14B, 984) in acetone (5 mL) at 0° C.was added 1-chloroethyl chloroformate (0.37 mL, 3.38 mmol). This mixturewas stirred at 0° C. for 2 h, warmed to room temperature, andconcentrated. The residue was purified by flash column chromatography(1025% ethyl acetate/hexanes) to give the intermediate carbamate whichwas refluxed in methanol (2 mL) for 30 min. Evaporation of the reactionmixture provided 128 mg (31%) of the title compound of Example 264, StepA as a white solid. ¹H NMR (CD₃OD, 400 MHz) δ 6.98 (dd, 1H), 6.88 (t,1H), 6.68-6.64 (c, 2H), 3.48-3.34 (c, 2H), 3.25-3.11 (c, 2H), 2.39-2.20(c, 4H); MS (APCI) 207 (MH⁺).

Step B:(R)-1-[4-(Spiro[benzothiazoline-2,4′-piperidine])-pyrimidin-2-yl]-ethylbutyrate. To a solution ofspiro[benzothiazolin-2,4′-piperidine]hydrochloride (prepared accordingto the method of Example 264, Step A, 147 mg, 0.60 mmol) in isopropanol(4 mL) was added (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate(prepared according to the method of Preparation Seven, 140 mg, 0.60mmol) followed by triethylamine (0.25 mL, 1.8 mmol). This mixture wasstirred at reflux for 2 h, concentrated, and purified by flash columnchromatography (1%→2% methanol/chloroform) to give 210 mg (88%) thetitle compound of Example 264, Step B as a yellow oil. ¹H NMR (CDCl₃,300 MHz) δ 8.20 (d, 1H), 7.09 (dd, 1H), 6.95 (t, 1H), 6.78 (t, 1H), 6.68(d, 1H), 6.40 (d, 1H), 5.68 (q, 1H), 4.32-4.18 (c, 2H), 4.02 (s, 1H),3.38-3.25 (c, 2H), 2.39 (t, 2 h), 2.36-2.25 (c, 2H), 1.99-1.83 (c, 2H),1.75-1.64 (c, 2H), 1.57 (d, 3H), 0.96 (t, 3H); MS (APCI) 399 (MH⁺).

Step C:(R)-1-[4-(Spiro[benzothiazoline-2,4′-piperidine])-pyrimidin-2-yl]-ethanol.A mixture of(R)-1-[4-(spiro[benzothiazoline-2,4′-piperidine])-pyrimidin-2-yl]-ethylbutyrate (prepared according to the method of Example 264, Step B, 204mg, 0.51 mmol) and lithium hydroxide hydrate (65 mg, 1.53 mmol) in a2:2:1 mixture of tetrahydrofuran/methanol/water (5 mL) was stirred atroom temperature for 1 h. The organic solvents were evaporated and theresidue was extracted with 10% isopropanol/chloroform (3×). The combinedorganic extracts were dried over sodium sulfate, filtered, evaporated,and purified by flash column chromatography (2% methanol/chloroform, 2×)to give a red foam which was further recyrstallized (ethyl acetate) togive 42 mg (25%) of the title compound as a yellow solid. ¹H NMR (CDCl₃,400 MHz) δ 8.18 (d, 1H), 7.07 (d, 1H), 6.93 (td, 1H), 6.78 (td, 1H),6.69 (d, 1H), 6.42 (d, 1H), 4.69 (m, 1H), 4.35-4.16 (c, 3H), 4.02 (s,1H), 3.41-3.28 (c, 2H), 2.37-2.24 (c, 2H), 1.99-1.85 (c, 2H), 1.49 (d,3H); MS (APCI) 329 (MH⁺); [α]_(D) +17.3 (c 1.0, MeOH).

Example 265

4-[2-(1R-Hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazine-1-carboxylicacid methyl ester.

To a solution of1R-[4-(2R,6S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl butyrate(prepared according to the procedure of Preparation Four, 70 mg, 23pmol) in tetrahydrofuran (2 mL) at room temperature under nitrogen wasadded triethylamine (63 μL, 46 pmol) followed by methyl chloroformate(21 μL, 27 pmol). This mixture was stirred for 1 h and concentrated. Theresidue was dissolved in a 3:1:1 mixture ofmethanol/tetrahydrofuran/water (2 mL) and lithium hydroxide hydrate (29mg, 69 pmol) was added. This mixture was stirred for 1 h, concentrated,re-suspended in water, and extracted with 10% isopropanol/chloroform(4×). The combined organic extracts were washed with saturated aqueoussodium bicarbonate (1×), dried over sodium sulfate, filtered, andevaporated to give 50 mg (74%, 2 steps) of the title compound as acolorless oil. ¹H NMR (CDCl₃, 400 MHz) δ 8.21 (d, 1H), 6.33 (d, 1H),4.70 (m, 1H), 4.63-3.912 (c, 5H), 3.76 (s, 3H), 3.20-3.012 (c, 2H), 1.50(d, 3H), 1.25 (d, 6H); MS (APCI), 295 (MH⁺); [α]^(D) +19.0 (c 0.9,MeOH).

Example 266

1R-(4-{4-[2-(1k-Butyryloxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethylbutyrate.

To a solution of1R-[4-(2R,6S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl butyrate(prepared according to the procedure of Preparation Four, 200 mg, 0.65mmol) in isopropanol (2 mL) at room temperature was added triethylamine(0.18 mL, 1.31 mmol) followed by (R)-1-(4-chloro-pyrimidin-2-yl)-ethylbutyrate (prepared according to the procedure of Preparation Seven, 150mg, 0.65 mmol). This mixture was heated to reflux for 18 h, cooled toroom temperature, concentrated and purified by flash columnchromatography (1% methanol/chloroform) to give 321 mg (99%) of thetitle compound as a yellow oil. ¹H NMR (CDCl₃, 400 MHz) δ 8.22 (d, 2H),6.43 (d, 1H), 6.32 (d, 1H), 5.68 (q, 2H), 4.72-4.24 (c, 4H), 3.30-3.12(c, 2H), 2.39 (t, 4H), 1.77-1.63 (c, 4H), 1.57 (d, 6H), 1.28-1.17 (c,6H), 0.96 (t, 6H); MS (APCI) 499 (MH⁺).

Example 267

4-{4-[2-(1R-Hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-6-methyl-[1.3.5]triazin-2-ol.

1R-{4-[4-(4-Chloro-6-methyl-[1,3,5]triazin-2-yl)-3R,5S-dimethylpiperazin-1-yl]-pyrimidin-2-yl}-ethylbutyrate (prepared according to the method of Example 213, Step A, 0.30g, 0.70 mmol) was added to concentrated hydrochloric acid (3 mL) andheated to reflux for 12 h. The mixture was neutralized to pH 7 withsolid sodium bicarbonate and extracted into chloroform. The organicextract was dried over sodium sulfate and filtered. The filtrate wasconcentrated to an oil which was purified by flash chromatography (92:8chloroform:methanol) to give the title compound as a white solid, 0.15 g(64%). ¹H NMR (CDCl₃, 300 MHz) δ 1.21 (d, 6H), 1.49 (d, 3H), 2.36 (s,3H), 3.21-3.27 (m, 2H), 4.22-4.43 (m, 2H), 4.63 (m, 2H), 4.69 (q, 1H),6.42 (d, 1H), 8.18 (d, 1H); mp: 247-248° C.; MS (CI) 346 (MHz).

Examples 268 to 275

Examples 268 to 275 were prepared from the appropriate startingmaterials in a manner analogous to the method of Example 267.

Example R¹¹ R⁶ R⁷ mp (° C.) MS (MH⁺) 268 H 3R-Me 5S-Me >250 332 269isopropyl 3R-Me 5S-Me >250 374 270 cyclohexyl 3R-Me 5S-Me >250 414 271phenyl 3R-Me 5S-Me >250 408 272 cyclopropyl 3R-Me 5S-Me >250 372 273methyl 2R-Me 6S-Me >250 346 274 cyclopropyl 2R-Me 6S-Me >250 372 275phenyl 2R-Me 6S-Me >250 408

Example 276

(E)-[4-Oxo-3-(5-trifluoromethyl-benzothiazol-2,ylmethyl)-3,4-dihydro-phthalazin-1-yl]-aceticacid1R-{4-[4-(3-thiophen-2-yl-acryloyl)-piperazin-1-yl]-pyrimidin-2-yl}-ethylester.

To a solution of[4-oxo-3-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-3,4-dihydro-phthalazin-1-yl]-aceticacid (0.59 g, 1.41 mmol) in dichloromethane (30 mL) and4-dimethylaminopyridine (0.18 g, 1.41 mmol) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.54 g,2.82 mmol) followed by(E)-1-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-piperazin-1-yl}-3-thiophen-2-yl-propenone(prepared according to the method of Example 127, 0.49 g, 1.41 mmol) atambient temperature and stirred for 20 h. The mixture was washed oncewith saturated aqueous sodium bicarbonate, once with saturated aqueoussodium chloride, dried over magnesium sulfate and filtered. The filtratewas concentrated to an oil which was purified by flash chromatography(ethyl acetate) to give the title compound as a white foam, 0.65 g(62%). ¹H NMR (CDCl₃, 300 MHz) δ 1.51 (d, 3H), 3.41-3.77 (m, 8H), 4.28(m, 2H), 5.18 (q, 1H), 5.79 (d, 1H), 6.35 (d, 1H), 6.68 (d, 1H), 7.05,(m, 1H), 7.32 (d, 1H), 7.68 (m, 1H), 7.71-7.90 (m, 5H), 8.18 (d, 1H),8.27 (d, 1H), 8.46 (m, 1H); mp: 105-109° C.; MS (CI) 746 (MH⁺); [α]_(D)+49.2 (c 1.0, MeOH).

Example 277

(E)-[4-Oxo-3-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-3,4-dihydro-phthalazin-1-yl]-aceticacid 1R-[4-(4-quinoxalin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethylester.

Example 277 was prepared from the appropriate starting materials in amanner analogous to the method of Example 276. ¹H NMR (CDCl₃, 300 MHz) δ1.53 (d, 3H), 3.38-3.87 (m, 8H), 4.28 (m, 2H), 5.18 (q, 1H), 6.35 (d,1H), 7.68 (m, 1H), 7.68-7.94 (m, 8H), 8.18 (d, 1H), 8.21-8.37 (m, 2H),8.46 (m, 1H); mp: 108-112° C.; MS (CI) 738 (MH⁺).

2-Methoxymethyl-4-piperazin-1-yl-pyrimidine.

Step A: 2-Methoxmethyl-pyrimidin-4-1-methanesulfonate. To an ice coldsolution of 2-methoxymethyl-3H-pyrimidin-4-one (35.0 g, 250 mmol; U.S.Pat. No. 5,215,990) and triethylamine (25.6 g, 250, mmol) indichloromethane (250 mL) was added methanesulfonyl chloride (28.6 g, 250mmol) dropwise. This mixture was allowed to warm slowly to roomtemperature over 1 h then washed successively with saturated aqueoussodium bicarbonate and water. The organic layer was dried over magnesiumsulfate, filtered, and evaporated to give the title compound ofPreparation One, Step A as a tan solid, 49.2 g (90%). ¹H NMR (CDCl₃, 300MHz) δ 3.55 (s, 3H), 3.82 (s, 3H), 4.42 (s, 2H), 6.36 (d, 1H), 8.12 (d,1H); mp: 39-40° C.; MS (TS) 219 (MH⁺).,

Step B: 2-Methoxymethyl-4-piperazin-1-yl-pyrimidine. To a solution of2-methoxymethyl-pyrimidin-4-yl-methanesulfonate (prepared according tothe method of Preparation One, Step A, 43.6 g, 200 mmol) intetrahydrofuran (400 mL) was added piperazine (34.4 g, 400 mmol). Thismixture was heated to reflux for 0.5 h, cooled to room temperature, andfiltered. The filtrate was concentrated and dried under reduced pressureto give the title compound as a semi-solid, 36.6 g (85%). ¹H NMR (CDCl₃,300 MHz) δ 2.45 (br s, 1H), 2.88 (m, 4H), 3.45 (s, 3H), 3.72 (m, 4H),4.46 (s, 2H), 6.38 (d, 1H), 8.22 (d, 1H); MS (TS) 209 (MH⁺).

Preparation Two

(R)-1-(4-piperazin-1-yl-pyrimidin-2-yl)-ethyl acetate. A mixture of(R)-1-(4-methanesulfonyloxy-pyrimidin-2-yl)-ethyl acetate (preparedaccording to the method of Preparation Six, 24.1 g, 92 mmol) andpiperazine (16.0 g, 184 mmol) in tetrahydrofuran (200 mL) was heated atreflux for 1 h. This mixture was cooled, filtered, concentrated, andpurified by flash column chromatography (9:1 dichloromethane/methanol)to give 24.4 g (88%) of the title compound as an oil. ¹H NMR (CDCl₃, 300MHz) δ 1.56 (d, 3H), 2.25 (s, 3H), 2.83 (m, 4H), 3.63 (m, 4H), 5.54 (q,1H), 6.38 (d, 1H), 8.24 (d, 1H); MS (CI) 251 (MH⁺).

Preparation Three

1R-[4-(3R,5S-Dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl butyrate. Amixture of (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (preparedaccording to the method of Preparation Seven, 18.5 g, 80.9 mmol) andcis-2,6-dimethylpiperazine (18.6 g, 162 mmol) in tetrahydrofuran (400mL) was stirred at room temperature overnight, diluted with ether, andwashed with saturated aqueous sodium bicarbonate (1×) and water (3×).The combined aqueous extracts were back-extracted with 10%isopropanol/chloroform (6×). The combined organic extracts were driedover sodium sulfate, filtered, evaporated, and purified by flash columnchromatography (15%, methanol/chloroform) to give 20.9 g (84%) of thetitle compound as a waxy yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.14(d, 1H), 6.31 (d, 1H), 5.65 (q, 1H), 4.53-4.16 (c, 2H), 2.89-2.78 (c,2H), 2.47-2.33 (c, 2H), 2.38 (t, 2H), 1.73-1.60 (c, 2H), 1.55 (d, 3H),1.11 (d, 6H), 0.94 (t, 3H); MS (APCI) 307 (MH⁺).

Preparation Four

1R-[4-(2R,6S-Dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl butyrate.

Step A:1-[4-(4-Benzyl-2R,6S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethylbutyrate.

A mixture of (R)-1-(4-trifluoromethanesulfonyloxy-pyrimidin-2-yl)-ethylbutyrate (prepared according to the method of Preparation Nine, 84.8 g,248 mmol) and cis-1-benzyl-3,5-dimethyl-piperazine (101 g, 496 mmol,Org. Prep. Proceed. Int 1976, 8, 19) in acetonitrile (310 mL) wasstirred at reflux for 15 h, concentrated, and purified, by flash columnchromatography (15% ethyl acetate/hexanes) to give 52 g (53%) of thetitle compound of Preparation Four, Step A as an orange oil. ¹H NMR(CDCl₃, 400 MHz) δ 8.15 (d, 1H), 7.39-7.24 (c, 5H), 6.25 (d, 1H), 5.66(q, 1H), 4.45 (m, 1H), 4.24 (m, 1H), 3.52 (s, 2H), 2.73 (d, 2H), 2.37(t, 2H), 2.22 (d, 2H), 1.70-1.60 (c, 2H), 1.55 (d, 3H), 1.30 (d, 3H),1.27 (d, 3H), 0.93 (t, 3H); MS (APCI) 398 (MH⁺).

Step B:1R-[4-(4-Benzyl-2R,6S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethylbutyrate and1S-[4-(4-Benzyl-2R,6S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethylbutyrate.1-[4-(4-Benzyl-2R,6S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethylbutyrate (prepared according to the method of Preparation Four, Step A,131 g, 79% ee) was purifed by chiral HPLC under the following conditions(column: 15 cm id×25 cm Prochrom column packed with Chiracel AD obtainedfrom Chiral Technologies Inc., 730 Springdale Dr., Exton, Pa., 19341;mobile phase: 90:10 n-heptane/isopropanol; flow rate: about 1 L/min;loading: 4.2 g/cycle) to provide the title compounds of PreparationFour, Step B (109 g, >98% ee) and (12.6 g, 93% ee), respectively, bothas yellow oils. The ¹H NMR and MS data for the preceding compounds werein agreement with that for scalemic material of Preparation Four, StepA.

Step C:1R-[4-(4-Benzyl-2R,6S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethylbutyrate hydrochloride. To a solution of1R-[4-(4-benzyl-2R,6S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethylbutyrate (prepared according to the method of Preparation Four, Step B,109 g, 275 mmol) in methanol (500 mL) was added hydrogen chloride (5 Min methanol, 56 mL, 278 mmol). This mixture was stirred at roomtemperature for 5 min and concentrated to give 118 g (99%) of the titlecompound of Preparation Four, Step C as a slightly yellow foam.

Step D: 1R[4-(2R,6S-Dimethyl-piperazin-1-yl)pyrimidin-2-yl]-ethylbutyrate. To a solution of1R-[4-(4-benzyl-2R,6S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethylbutyrate hydrochloride (prepared according to the method of PreparationFour, Step C, 54.2 g, 125 mmol) in methanol (200 mL) was added ammoniumformate (79 g, 1.25 mol) followed by a slurry of 10% palladium on carbon(13.5 g, 25 wt %) in methanol (200 mL). This mixture was stirred atreflux for 1 h and filtered through Celite. The filtrate wasconcentrated, diluted with saturated aqueous sodium bicarbonate, andextracted with chloroform (2×). The combined organic extracts were driedover sodium sulfate, filtered, and evaporated to give 40.8 g of thetitle compound as a yellow oil. ¹H NMR (CDCl₃, 400 MHz) δ8.16 (d, 1H),6.26 (d, 1H), 5.66 (q, 1H), 4.39 (m, 1H), 4.22 (m, 1H), 2.93 (app s,4H), 2.38 (t, 2H), 1.71-1.62 (c, 2H), 1.56 (d, 3H), 1.27 (d, 3H), 1.24(d, 3H), 0.94 (t, 3H); MS (APCI) 307 (MH⁺).

Preparation Five

(R)-1-(4-Chloro-pyrimidin-2-yl)-ethyl acetate.(R)-2-(1-Acetoxy-ethyl)-3H-pyrimidin-4-one (prepared according to themethod of Preparation Thirteen, 3.00 g, 16.5 mmol) was added tophosphorus oxychloride (10 mL) at ambient temperature and stirred for 3h. Excess phosphorus oxychloride was removed under vacuum and theresulting oil was partitioned between chloroform and saturated aqueoussodium carbonate. The layers were separated and the organic layer waswashed twice with water, once with saturated aqueous sodium chloride anddried over magnesium sulfate and filtered. The filtrate was evaporatedto give the title compound as an orange oil, 2.88 g (87%). ¹H NMR(CDCl₃, 300 MHz) δ 1.56 (d, 3H), 2.18 (s, 3H), 5.68 (q, 1H), 6.32 (d,1H), 8.21 (d, 1H); MS (CI) 201, 203 (MH⁺); [α]_(D) +27.6 (c 1.0, MeOH).

Preparation Six

(R)-1-(4-Methanesulfonyloxy-pyrimidin-2-yl)-ethyl acetate. To an icecold solution of (R)-2-(1-acetoxy-ethyl)-3H-pyrimidin-4-one (preparedaccording to the method of Preparation Thirteen, 2.58 g, 14.2 mmol) andtriethylamine (1.43 g, 14.2 mmol) in dichloromethane (20 mL) was addedmethanesulfonyl chloride (1.63 g, 14.2 mmol) dropwise and stirred for 1h. The mixture was washed successively with saturated aqueous sodiumbicarbonate and water, dried over magnesium sulfate and filtered. Thefiltrate was evaporated to give the title compound as an oil, 3.15 g(85%). ¹H NMR (CDCl₃, 300 MHz) δ 1.56 (d, 3H), 2.18 (s, 3H), 3.82 (s,3H), 5.56 (q, 1H), 6.38 (d, 1H), 8.24 (d, 1H); MS (CI) 261 (MH⁺);[α]_(D) +53.8 (c 1.1, MeOH).

Preparation Seven

(R)-1-(4-Chloro-pyrimidin-2-yl)-ethyl butyrate.(R)-2-(1-Butyryloxy-ethyl)-3H-pyrimidin-4-one (prepared according to themethod of Preparation Fourteen, 3.00 g, 16.5 mmol) was added tophosphorus oxychloride (10 mL) at ambient temperature and stirred for 3h. Excess phosphorus oxychloride was removed under vacuum and theresulting oil was partitioned between dichloromethane and saturatedaqueous sodium carbonate. The layers were separated and the organiclayer was washed once with water, once with saturated aqueous sodiumchloride and dried over magnesium sulfate and filtered. The filtrate wasevaporated to give the title compound as an orange oil, 3.19 g (85%). ¹HNMR (CDCl₃, 300 MHz) δ 0.98 (t, 3H), 1.54 (d, 3H), 1.67 (m, 2H), 2.48(t, 2H), 5.68 (q, 1H), 6.36 (d, 1H), 8.21 (d, 1H); [α]_(D) +27.6 (c 1.0,MeOH).

Preparation Eight

(R)-1-(4-Methanesulfonyloxy-pyrimidin-2-yl)-ethyl butyrate. To an icecold solution of (R)-2-(1-butyryloxy-ethyl)-3H-pyrimidin-4-one (preparedaccording to the method of Preparation Fourteen, 17.8 g, 97.8 mmol) andtriethylamine (9.9 g, 97.8 mmol) in dichloromethane (100 mL) was addedmethanesulfonyl chloride (11.21 g, 97.8 mmol) dropwise and stirred for 1h. The mixture was washed successively with saturated aqueous sodiumbicarbonate and water, dried over magnesium sulfate and filtered. Thefiltrate was evaporated to give the title compound as an oil, 24.1 g(94%). ¹H NMR (CDCl₃, 300 MHz) δ 0.99 (t, 3H), 1.54 (d, 3H), 1.68 (m,2H), 2.48 (t, 2H), 3.81 (s, 3H), 5.54 (q, 1H), 6.38 (d, 1H), 8.24 (d,1H); MS (CI) 261 (MH⁺); [α]_(D) +28.8 (c 1.0, MeOH).

Preparation Nine

(R)-1-(4-Trifluoromethanesulfonyloxy-pyrimidin-2-yl)-ethyl butyrate.

Method 1: To a solution of (R)-2-(1-butyryloxy-ethyl)-3H-pyrimidin-4-one(prepared according to the method of Preparation Fourteen, 52 g, 248mmol) and triethylamine (36.2 mL, 260 mmol) in dichloromethane (830 mL)at 0° C. with stirring under nitrogen atmosphere was added a solution oftrifluoromethanesulfonic anhydride (44 mL, 260 mmol) in dichloromethane(70 mL) dropwise via addition funnel over 30 min, maintaining aninternal temperature of 4-8° C. This mixture was allowed to stir anadditional 15 min at 4° C., then quenched with water. After stirring for10 min, the layers were separated and the aqueous layer was extractedwith dichloromethane (3×). The combined organic extracts were dried oversodium sulfate, filtered, and concentrated to give 47.2 g (−100%) of thetitle compound as a dark oil which was used immediately in the nextstep. ¹H NMR (CDCl₃, 400 MHz) δ 8.83 (d, 1H), 7.03 (d, 1H), 5.82 (q,1H), 2.41-2.32 (c, 2H), 1.72-1.60 (c, 2H), 1.62 (d, 3H), 0.95 (t, 3H);MS (APCI) 343 (MH⁺).

Method 2: To a solution of (R)-2-(1-butyryloxy-ethyl)-3H-pyrimidin-4-one(prepared according to the method of Preparation Fourteen, 4.20 g, 0.0mmol) and triethylamine (2.02 g, 20.0 mmol) in dichloromethane (20 mL)was added trifluoromethanesulfonyl chloride (3.37 g, 20.0 mmol)dropwise, maintaining an internal temperature less than −20° C., andstirred for, 0.5 h. The mixture was washed successively with saturatedaqueous sodium bicarbonate and water, dried over sodium sulfate andfiltered. The filtrate was evaporated to give the title compound as adark oil, 6.42 g (94%), which was used immediately in the next step. ¹HNMR and MS data were were in agreement with that from Preparation Nine,Method 1.

Preparation Ten

(R)-1-(4-Chloro-pyrimidin-2-yl)-ethanol. To a solution of(R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according tothe method of Preparation Seven, 250 mg, 1.1 mmol) in, dioxane (0.9 mL)was added concentrated hydrochloric acid (0.9 mL). This mixture wasallowed to stir at room temperature for 5 h, quenched with saturatedaqueous sodium bicarbonate followed by solid sodium bicarbonate until nomore gas evolution was evident. Dichloromethane was added and the layerswere separated. The aqueous phase was extracted with dichloromethane(3×) and the combined organic extracts were dried over sodium sulfate,filtered, and evaporated to give 125 mg (71%) of the title compound as apale yellow oil. ¹H NMR (CDCl₃, 400 MHz) δ 8.59 (d, 1H), 7.25 (d, 1H),4.92 (q, 1H), 3.81 (br s, 1H), 1.56 (d, 3H); MS (APCI) 159, 161 (MH⁺).

Preparation Eleven

(R)-(+)-2-(1-Hydroxy-ethyl)-3H-pyrimidin-4-one hydrochloride.

Step A: R-(+)-2-Hydroxy-propionamidine hydrochloride. To a 22 L, 3-neckround bottom flask equipped with reflux condenser, mechanical stirrer,thermometer and nitrogen inlet was added tetrahydrofuran (7.3 L),R-(+)-2-hydroxy-propionamide (731 g, 8.2 mol) and triethyloxoniumtetrafluoroborate (95%, 1.97 kg, 9.8 mol). The resulting yellow solutionwas allowed to stir at room temperature for 2 h, at which time an NMRsample indicated consumption of starting material and the presence ofthe desired imidate. The solution was concentrated under vacuum toprovide a yellow oil which was taken up in methanol (2 L). This solutionwas cooled to 15° C. and anhydrous ammonia was bubbled through thesolution for 5 h. The resulting suspension was allowed to stir for 2 h.concentrated to a thick mixture, diluted with ethyl acetate and filteredthrough Celite. The filtrate was then cooled to 10° C., anhydroushydrogen chloride was bubbled through the solution for 2 h, warmed toroom temperature, and filtered to provide 418 g (41%) of the titlecompound of Preparation Eleven, Step A. mp: 134-138° C.; ¹H NMR(DMSO-d₆, 300 MHz) δ 1.33° (t, 3H), 4.42 (q, 1H), 6.25-6.88 (br s, 1H),8.72-9.25 (br s, 3H).

Step B: (R)-(+)-2-(1-Hydroxy-ethyl)-3H-pyrimidin-4-one hydrochloride. Toa 22 L, 3-neck round bottom flask equipped with a reflux condenser,mechanical stirrer, thermometer and nitrogen inlet was added methanol (8L), potassium hydroxide (946 g, 14.7 mol),R-(+)-2-hydroxy-propionamidine (prepared according to the method ofPreparation Eleven, Step A, 1848 g, 14.7 mol) and ethyl3-hydroxy-acrylate sodium salt (prepared according to the method ofPreparation Twelve, Step C, 2030 g, 14.7 mol). The resulting slurry wasstirred at room temperature for 13 h. The pH was adjusted from 12.5 to 7by the addition of concentrated hydrochloric acid (1.32 L). The solidswere filtered off and washed with isopropanol. The filtrate wasconcentrated to an oil, diluted with isopropanol (4 L), cooled to 10° C.and anhydrous hydrogen chloride was bubbled through the solution for 4h. The resulting suspension was filtered and the solids were dried toprovide 2242 g (87%) of the title compound. mp: 180-184° C. (dec); ¹HNMR (DMSO-d₆, 400 MHz) δ1.46 (d, 3H), 4.84 (q, 1H), 6.52 (d, 1H), 8.00(d, 1H).

Preparation Twelve

2-(1-Hydroxy-ethyl)-3H-pyrimidin-4-one.

Step A: 2-Hydroxy-propionimidic acid ethyl ester hydrochloride. Asolution of lactonitrile (378 g, 5.32 mol) in ethyl ether (1.46 L) andethanol (0.34 L) was saturated with hydrogen chloride gas at 0-5° C. for0.5 h and kept at 5° C. for 60 h. The resulting precipitate was filteredoff and washed twice with ethyl ether to give the title compound ofPreparation Twelve, Step A as a solid, 815 g (99%). mp: 165-168° C.; ¹HNMR (CD₃OD, 250 MHz) δ 1.45-1.53 (c, 6H), 4.40-4.61 (c, 3H).

Step B: 2-Hydroxy-propionamidine hydrochloride. A suspension of2-hydroxypropionimidic acid ethyl ester hydrochloride (preparedaccording to the method of Preparation Twelve, Step A, 751 g, 4.87 mol)in ethanol (3.75 L) at 0° C. was saturated with ammonia gas, maintainingan internal temperature≦5° C., for 1 h then stirred at ambienttemperature for 18 h. The solid was filtered off and dried under vacuumat 40° C. to give an initial crop of material. The filtrate wasconcentrated to one-half volume and a second crop was collected anddried under vacuum. The first and second crops were combined to give thetitle compound of Preparation Twelve, Step B as a yellow solid, 608 g(99%) mp: 134-138° C.; ¹H NMR (DMSO-d₆, 400 MHz) δ 1.30 (d, 3H), 4.38(q, 1H), 6.23 (br s, 1H), 7.35 (br s, 1H), 8.78 (br s, 3H).,

Step C: Ethyl 3-hydroxy-acrylate sodium salt. To a suspension of sodiumhydride (60% dispersion in oil, 269 g, 16.7 mol) in isopropyl ether (12L) was added slowly ethyl acetate (1280 g, 14.2 mol) at a rate whichmaintained an internal temperature of 45° C. This mixture was stirredfor and additional 0.5 h, then ethyl formate (2232 g, 30.1 mol) wasadded dropwise at 42° C. and stirred at ambient temperature for 18 h.The mixture was filtered and the solids were washed twice with ethylether and once with hexanes and dried to give the title compound ofPreparation Twelve, Step C as a white solid, 1930 g (99%). ¹H NMR(DMSO-d₆, 300 MHz) δ 1.03 (t, 3H), 3.86 (q, 2H), 4.08 (d, 1H), 8.03 (d,1H).

Step D: 2-(1-Hydroxy-ethyl)-3H-pyrimidin-4-one. To a solution of ethyl3-hydroxy-acrylate sodium salt (prepared according to the method ofPreparation Twelve, Step C, 1301 g, 9.42 mol) in water (1.3 L) was addeda solution of 2-hydroxy-propionamidine hydrochloride (prepared accordingto the method of Preparation Twelve, Step B, 610 g, 4.9 mol) in water(1.3 L) at ambient temperature and stirred, for 48 h. The solution wasadjusted to pH 7.0 with acetic acid then continuously extracted withchloroform for 48 h. The extract was dried over sodium sulfate andfiltered. The filtrate was concentrated to a solid, slurried in ethylether, filtered, and dried to give the title compound as a solid, 232 g(38%). mp: 121-124° C.; ¹H NMR (DMSO-d₆, 400 MHz) δ 1.30 (d, 3H), 4.46(q, 1H), 5.62 (br s, 1H), 6.13 (d, 1H), 7.80 (d, 1H).

Preparation Thirteen

(R)-2-(1-Acetoxy-ethyl)-3H-pyrimidin-4-one. To a solution of vinylacetate (4.3 g, 50 mmol) in dioxane (63 mL) was added2-(1-hydroxy-ethyl)-3H-pyrimidin-4-one (prepared according to the methodof Preparation Twelve, 2.1 g, 15.1 mmol), and the mixture was heated to50° C. To the resulting solution was added lipase P30 (0.21 g, 10 wt %)and the heating was continued for 24 h. The reaction mixture wasfiltered and the filtrate was evaporated to obtain a thick syrupy liquidresidue. The residue was purified by flash column chromatography (95:5dichloromethane:methanol) to give the title compound as a colorlessliquid, 0.97 g (92% of theory). ¹H NMR (CDCl₃, 300 MHz) δ 1.61 (d, 3H),2.20 (s, 3H), 5.65 (q, 1H), 6.35 (d, 1H), 7.97 (d, 1H), 11.94 (s, 1H);[α]_(D) +39.9 (c 1.0, MeOH).

Preparation Fourteen

(R)-2-(1-Butyryloxy-ethyl)-3H-pyrimidin-4-one.

Method 1: To a solution of vinyl butyrate (17.7 g, 310 mmol) in dioxane(650 mL) was added 2-(1-hydroxy-ethyl)-3H-pyrimidin-4-one (preparedaccording to the method of Preparation Twelve, 21.8 g, 155 mmol), andthe mixture was heated to 50° C. To the resulting solution was addedlipase P30 (4.35 g, 20 wt %) and the heating was continued for 24 h. Thereaction mixture was filtered and the filtrate was evaporated to obtaina thick syrupy liquid residue which was partitioned betweendichloromethane and water. The layers were separated and the organiclayer was dried over sodium sulfate, filtered, and evaporated to givethe title compound as a colorless liquid, 9.35 g (86% of theory). ¹H NMR(CDCl₃, 300 MHz) 0.95 (t, 3H), 1.65 (m, 5H), 2.40 (m, 2H), 5.65 (q, 1H),6.45 (d, 1H), 8.00 (d, 1H); [α]_(D) +29.5 (c 1.0, MeOH).

Method 2: To a chilled (5° C.) solution of(R)-(+)-2-(1-hydroxy-ethyl)-3H-pyrimidin-4-one hydrochloride (preparedaccording to the method of Preparation Eleven, 750 g, 4.3 mol) indichloromethane (8 L) was added triethylamine (1216 mL, 8.7 mol)followed by 4-dimethylaminopyridine (25.9 g, 0.21 mol). A solution ofbutyric anhydride (730 mL, 4.4 mol) in dichloromethane (730 mL) was thenslowly added over a period of 5 h, keeping the temperature≦3° C. Themixture was washed twice with half-saturated brine (4 L) and once withsaturated aqueous sodium bicarbonate (4 L), dried over sodium sulfate,filtered, and concentrated under vacuum to give 869 g (96%) of the titlecompound as an oil. The ¹H NMR and MS data for this compound are inagreement with that of Preparation Fourteen, Method 1.

Preparation Fifteen

1R-[4-(2R,6S-Dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl butyratedibenzoyl-L-tartrate salt.

Step A:1R-[4-(4-Benzyl-2R,6S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethylbutyrate bis dibenzoyl-L-tartrate salt. To a solution of(R)-2-(1-butyryloxy-ethyl)-3H-pyrimidin-4-one (prepared according to themethod of Preparation Fourteen, 254 g, 1.25 mol) and triethylamine (176mL, 1.3 mol) in dichloromethane (2.3 L) at 5° C. was slowly added asolution of trifluoromethanesulfonic anhydride (211 mL, 1.25 mol) indichloromethane (355 mL) over a period of 3 h. The reaction was thenquenched by the addition of cold water (1.4 L) and the layers wereseparated. The organic layer was washed once with saturated aqueoussodium bicarbonate (1.5 L), once with saturated aqueous sodium chloride(1 L), and the solvent was removed under vacuum. The resulting oil wasdissolved in dimethylacetamide (890 mL) and added slowly to a solutionof cis-1-benzyl-3,5-dimethyl-piperazine (735 g, 3.6 mol) indimethylacetamide (11.3 L) at 80° C. over a 1 h, period. Heating at 80°C. was continued for 3.5 h, at which time the reaction was judgedcomplete by gas chromatography. After cooling to room temperature, water(2.5 L) and isopropyl ether (2.5 L) were added, the layers wereseparated, and the organic layer was washed once with water (2 L). Theisopropyl ether layer was then mixed well with a solution of CuSO₄ (126g) in water (3 L) and filtered through a layer of Celite, washing thefilter cake with isopropyl ether (1 L). The aqueous layer of thefiltrate was drained off, and the, remaining organic layer was washedwith water (2 L) and treated with a solution of dibenzoyl-L-tartaricacid (619 g, 2.4 mol) in isopropyl ether (5.3 L). The resulting thickwhite slurry was stirred for 16 h and the solids were filtered off,washed with isopropyl ether (2 L), and vacuum dried at 50° C. to yield854 g (71%) of the title compound of Preparation Fifteen, Step A as awhite solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 0.89 (t, 3H), 1.23 (d, 3H),1.25 (d, 3H), 1.48 (d, 3H), 1.54 (dd, 2H), 2.20 (dd, 2H), 2.31 (dt, 2H),2.77 (d, 2H), 3.57 (s, 1H), 4.45 (m, 1H), 4.24 (m, 1H), 5.51 (q, 1H),6.60 (d, 1H), 7:30 (m, 1H), 7.39 (m, 4H), 7.64 (m, 7H), 7.77 (m, 4H),8.05 (c, 7H), 8.17 (d, 1H).

Step B: 1R-[4-(2R,6S-Dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethylbutyrate dibenzoyl-L-tartrate salt. To a mixture of1R-[4-(4-benzyl-2R,6S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethylbutyrate bis dibenzoyl-L-tartrate salt (prepared according to the methodof Preparation Fifteen, Step A, 50 g, 0.045 mol) and 5% palladium oncarbon (50% wet, 10 g, 20 wt %) in methanol (400 mL) under a nitrogenatmosphere was added cyclohexene (4.6 mL, 0.045 mol). This mixture washeated to reflux for 6 h, at which time the reaction was judged completeby TLC. After cooling to 40° C., the mixture was filtered through Celiteand washed with methanol (100 mL). The methanol was gradually displacedwith isopropanol by atmospheric pressure distillation until a constantboiling point of 80-82° C. was attained, and the resulting white slurrywas cooled to room temperature and stirred for 4 h. The solids werefiltered off, washed with isopropanol (100 mL), and vacuum dried at 50°C. to yield 25.7 g (86%) of the title compound as a white solid. ¹H NMR(DMSO-d₆, 400 MHz) δ 0.90 (t, 3H), 1.15 (d, 3H), 1.21 (d, 3H), 1.47 (d,3H), 1.55 (q, 2H), 2.3 (m, 2H), 3.04 (m, 2H), 3.2 (m, 2H), 4.4 (br s,1H), 4.6 (br s, 1H), 5.5 (q, 1H), 5.74 (s, 2H), 6.6 (d, 1H), 7.5 (t,4H), 7.6 (m, 2H), 8.0 (m, 4H), 8.2 (d, 1H).

1. A compound of the formula I

a prodrug thereof or a pharmaceutically acceptable salt of said compoundor said prodrug, wherein: R¹ is formyl, acetyl, propionyl, carbamoyl or—C(OH)R⁴R⁵; R⁴ and R⁵ are each independently hydrogen, methyl, ethyl orhydroxy-(C₁-C₃)alkyl; R² is hydrogen, (C₁-C₄)alkyl or (C₁-C₄)alkoxy; R³is

R²⁷ is hydrogen or (C₁-C₄)alkyl; R²⁸ and R²⁹ are each independentlyhydrogen, hydroxy, halo, hydroxy-(C₁-C₄)alkyl,(C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally substituted with upto five fluoro, (C₁-C₄)alkoxy optionally substituted with up to fivefluoro, phenyl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl,oxazolyl, phenoxy, thiophenoxy, SO₂NR³⁰R³¹, CONR³⁰R³¹ or NR³⁰R³¹; saidthienyl, pyrimidyl, furanyl, thiazolyl and oxazolyl in the definition ofR²⁸ and R²⁹ are optionally substituted by up to two hydroxy, halo,hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyloptionally substituted with up to five fluoro or (C₁-C₄)alkoxyoptionally substituted with up to five fluoro; said phenyl, pyridyl,phenoxy and thiophenoxy in the definition of R²⁸ and R²⁹ are optionallysubstituted by up to three hydroxy, halo, hydroxy-(C₁-C₄)alkyl,(C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally substituted with upto five fluoro or (C₁-C₄)alkoxy optionally substituted with up to fivefluoro; R³⁰ and R³¹ are each independently hydrogen, (C₁-C₄)alkyl,(C₃-C₇)cycloalkyl or phenyl, said phenyl is optionally substituted withup to three hydroxy, halo, hydroxy-(C₁-C₄)alkyl,(C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyl optionally substituted with upto five fluoro or (C₁-C₄)alkoxy optionally substituted with up to fivefluoro; or R³⁰ and R³¹ are taken together with the nitrogen to whichthey are attached to form indolinyl, pyrrolidinyl, piperidinyl,piperazinyl or morpholinyl; said pyrrolidinyl and piperidinyl in thedefinition of R³⁰ and R³¹ are optionally substituted with up to twohydroxy, amino, hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl,(C₁-C₄)alkyl optionally substituted with up to five fluoro or(C₁-C₄)alkoxy optionally substituted with up to five fluoro; saidindolinyl and piperazinyl in the definition of R³⁰ and R³¹ areoptionally substituted with up to three hydroxy, amino,hydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxycarbonyl,(C₁-C₄)alkyl optionally substituted with up to five fluoro or(C₁-C₄)alkoxy optionally substituted with up to five fluoro; saidmorpholinyl in the definition of R³⁰ and R³¹ is optionally substitutedwith up to two substituents independently selected fromhydroxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkyloptionally substituted with up to five fluoro and (C₁-C₄)alkoxyoptionally substituted with up to five fluoro; 2-3. (Canceled)
 4. Acompound of claim 1, a prodrug thereof or a pharmaceutically acceptablesalt of said compound or said prodrug, wherein: R²⁷ is hydrogen; R²⁸ andR²⁹ are each independently hydrogen, hydroxy, halo, (C₁-C₄)alkyloptionally substituted with one to three fluoro, (C₁-C₄)alkoxy, phenyl,pyridyl, pyrimidyl, thienyl, phenoxy, thiophenoxy, SO₂NR³⁰R³¹, CONR³⁰R³¹or NR³⁰R³¹; said phenyl, pyridyl, in the definition of R²⁸ and R²⁹ areoptionally substituted by up to three hydroxy, halo, (C₁-C₄)alkyloptionally substituted with one to three up to five fluoro or(C₁-C₄)alkoxy optionally; and R³⁰ and R³¹ are each independentlyhydrogen or (C₁-C₄)alkyl. 5-114. (Canceled)
 115. A pharmaceuticalcomposition comprising a compound of claim 1, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug and apharmaceutically acceptable carrier or diluent.
 116. A method ofinhibiting sorbitol dehydrogenase in a mammal in need of such inhibitioncomprising administering to said mammal a sorbitol dehydrogenaseinhibiting amount of a compound of claim 1, a prodrug thereof or apharmaceutically acceptable salt of said compound or said prodrug. 117.A method of treating diabetes in a mammal suffering from diabetescomprising administering to said mammal an effective amount of acompound of claim 1, a prodrug thereof or a pharmaceutically acceptablesalt of said compound or said prodrug.
 118. A method of treating orpreventing diabetic complications in a mammal comprising administeringto said mammal an effective amount of a compound of claim 1, a prodrugthereof or a pharmaceutically acceptable salt of said compound or saidprodrug.
 119. A method of claim 118 wherein said mammal is sufferingfrom diabetes.
 120. A method of claim 118 wherein said diabeticcomplication is diabetic neuropathy.
 121. A method of claim 118 whereinsaid diabetic complication is diabetic nephropathy.
 122. A method ofclaim 118 wherein said diabetic complication is diabetic retinopathy.123. A method of claim 118 wherein said diabetic complication is footulcers.
 124. A method of claim 118 wherein said diabetic complication isa cardiovascular condition. 125-190. (Canceled)
 191. A compound of claim4 wherein R³ is


192. A compound of claim 191 wherein R²⁷ is hydrogen and R²⁸ and R²⁹ areeach independently hydrogen, methyl, ethyl, methoxy, phenyl, amino,phenoxy, phenylsulfanyl, dimethylamino, 4-pyridyl, 4-fluorophenyl,4-chlorophenyl or 4-methoxyphenyl.
 193. A compound of claim 191 which is(R)-1-[4-(2-methyl-4-phenyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl)-pyrimidin-2-yl-ethanol;(R)-1-[4-(2-phenyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl)-pyrimidin-2-yl]-ethanol;(R)-1-[4-(4-phenyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl)-pyrimidin-2-yl]-ethanol;(R)-1-[4-(2-ethyl-4-phenyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl)-pyrimidin-2-yl-ethanol;(R)-1-[4-(2-amino-4-phenyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl)-pyrimidin-2-yl-ethanol;(R)-1-[4-(5,8-dihydro-2,4-diphenyl-6H-pyrido[3,4-d]pyrimidin-7-yl)-pyrimidin-2-yl-ethanol;(R)-1-[4-(4-phenyl-2-pyridin-4-yl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl)-pyrimidin-2-yl]-ethanol;(R)-1-{4-[4-(4-methoxy-phenyl)-2-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl]-pyrimidin-2-yl}-ethanol;(R)-1-{4-[4-(4-fluoro-phenyl)-2-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl]-pyrimidin-2-yl}-ethanol;(R)-1-{4-[4-(4-chloro-phenyl)-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl]-pyrimidin-2-yl}-ethanol;(R)-1-[4-(4-methoxy-2-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl)-pyrimidin-2-yl]-ethanol;(R)-1-[4-(2-methyl-4-phenoxy-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl)-pyrimidin-2-yl]-ethanol;(R)—[4-(2-methyl-4-phenylsulfanyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl)-pyrimidin-2-yl]-ethanol;or(R)-1-[4-(4-dimethylamino-2-ethyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl)-pyrimidin-2-yl]-ethanol.194. A compound of claim 4 wherein R³ is


195. A compound of claim 194 wherein R²⁷ and R²⁹ are each hydrogen andR²⁸ is hydrogen, methyl, trifluoromethyl, amino, phenyl or pyridyl. 196.A compound of claim 194 which is(R)-1-[4-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)-pyrimidin-2-yl]-ethanol;(R)-1-[4-(2-methyl]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)-pyrimidin-2-yl]-ethanol;(R)-1-[4-(2-trifluoromethyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)-pyrimidin-2-yl]-ethanol;(R)-1-[4-(2-amino-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)-pyrimidin-2-yl]-ethanol;(R)-1-[4-(2-phenyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)-pyrimidin-2-yl]-ethanol;or(R)-1-[4-(2-pyridin-4-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)-pyrimidin-2-yl]-ethanol.197. A compound of claim 4 wherein R³ is


198. A compound of claim 197 wherein R²⁷ is hydrogen and R²⁸ and R²⁹ areeach independently hydrogen, dimethylaminosulfonyl, thienyl, pyrimidylor hydroxy.
 199. A compound of claim 197 which is(R)-2-[2-(1-hydroxy-ethyl)-pyrimidin-4-yl]-1,2,3,4-tetrahydro-isoquinoline-7-sulfonicacid dimethylamide;(R)-1-[4-(6-thiophen-3-yl-3,4-dihydro-1H-isoquinolin-2-yl)-pyrimidin-2-yl]-ethanol;(R)-1-[4-(6-thiophen-2-yl-3,4-dihydro-1H-isoquinolin-2-yl)-pyrimidin-2-yl]-ethanol;(R)-1-[4-(6-pyrimidin-5-yl-3,4-dihydro-1H-isoquinolin-2-yl)-pyrimidin-2-yl]-ethanol;(R)-1-[4-(7-pyrimidin-5-yl-3,4-dihydro-1H-isoquinolin-2-yl)-pyrimidin-2-yl]-ethanol;or(R)-2-[2-(1-hydroxy-ethyl)-pyrimidin-4-yl]-1,2,3,4-tetrahydro-isoquinolin-6-ol.